Array ( [0] => {{Short description|Family of proteins}} [1] => {{Distinguish|Actinium}} [2] => [3] => {{Infobox protein family [4] => | Symbol = Actin [5] => | Name = Actin [6] => | image =Actin with ADP highlighted.png [7] => | width = [8] => | caption = [[Ribbon diagram]] of G-actin. [[Adenosine diphosphate|ADP]] bound to actin's [[active site]] (multi color sticks near center of figure) as well as a complexed [[calcium in biology|calcium]] dication (green sphere) are highlighted. [9] => | Pfam =PF00022 [10] => | InterPro = IPR004000 [11] => | SMART = [12] => | PROSITE = PDOC00340 [13] => | SCOP =2btf [14] => | TCDB = [15] => | OPM family = [16] => | OPM protein = [17] => }} [18] => '''Actin''' is a [[protein family|family]] of [[Globular protein|globular]] multi-functional [[protein]]s that form [[microfilament]]s in the [[cytoskeleton]], and the thin filaments in [[myofibril|muscle fibrils]]. It is found in essentially all [[Eukaryote|eukaryotic cells]], where it may be present at a concentration of over 100 [[micromolar|μM]]; its mass is roughly 42 [[kDa]], with a diameter of 4 to 7 nm. [19] => [20] => An actin protein is the [[monomer]]ic [[Protein subunit|subunit]] of two types of filaments in cells: [[microfilaments]], one of the three major components of the cytoskeleton, and thin filaments, part of the [[Muscle contraction|contractile]] apparatus in [[muscle]] cells. It can be present as either a free [[monomer]] called '''G-actin''' (globular) or as part of a linear [[polymer]] microfilament called '''F-actin''' (filamentous), both of which are essential for such important cellular functions as the [[Motility|mobility]] and contraction of [[cell (biology)|cells]] during [[cell division]]. [21] => [22] => Actin participates in many important cellular processes, including [[#Muscle contraction|muscle contraction]], cell [[motility]], cell division and [[cytokinesis]], [[Vesicle (biology and chemistry)|vesicle]] and [[organelle]] movement, [[cell signaling]], and the establishment and maintenance of [[cell junction]]s and cell shape. Many of these processes are mediated by extensive and intimate interactions of actin with [[Cell membrane|cellular membranes]].{{cite journal | vauthors = Doherty GJ, McMahon HT | s2cid = 17352662 | title = Mediation, modulation, and consequences of membrane-cytoskeleton interactions | journal = Annual Review of Biophysics | volume = 37 | issue = 1 | pages = 65–95 | year = 2008 | pmid = 18573073 | doi = 10.1146/annurev.biophys.37.032807.125912 }} In vertebrates, three main groups of actin [[isoforms]], [[ACTA1|alpha]], [[ACTB|beta]], and [[ACTG1|gamma]] have been identified. The alpha actins, found in muscle tissues, are a major constituent of the contractile apparatus. The beta and gamma actins coexist in most cell types as components of the [[cytoskeleton]], and as [[chemical mediator|mediators]] of internal cell [[motility]]. It is believed that the diverse range of structures formed by actin enabling it to fulfill such a large range of functions is regulated through the binding of [[tropomyosin]] along the filaments.{{cite journal | vauthors = Vindin H, Gunning P | title = Cytoskeletal tropomyosins: choreographers of actin filament functional diversity | journal = Journal of Muscle Research and Cell Motility | volume = 34 | issue = 3–4 | pages = 261–274 | date = Aug 2013 | pmid = 23904035 | pmc = 3843815 | doi = 10.1007/s10974-013-9355-8 }} [23] => [24] => A cell's ability to dynamically form microfilaments provides the scaffolding that allows it to rapidly remodel itself in response to its environment or to the organism's internal [[signal transduction|signals]], for example, to increase cell membrane absorption or increase [[cell adhesion]] in order to form cell [[tissue (biology)|tissue]]. Other enzymes or [[organelle]]s such as [[Cilium|cilia]] can be anchored to this scaffolding in order to control the deformation of the external [[cell membrane]], which allows [[endocytosis]] and [[cytokinesis]]. It can also produce movement either by itself or with the help of [[molecular motors]]. Actin therefore contributes to processes such as the intracellular transport of [[Vesicle (biology and chemistry)|vesicles]] and organelles as well as [[muscle|muscular contraction]] and [[cell migration|cellular migration]]. It therefore plays an important role in [[embryogenesis]], the healing of wounds, and the invasivity of [[cancer]] cells. The evolutionary origin of actin can be traced to [[prokaryotic cells]], which have equivalent proteins.{{cite journal | vauthors = Gunning PW, Ghoshdastider U, Whitaker S, Popp D, Robinson RC | title = The evolution of compositionally and functionally distinct actin filaments | journal = Journal of Cell Science | volume = 128 | issue = 11 | pages = 2009–2019 | date = Jun 2015 | pmid = 25788699 | doi = 10.1242/jcs.165563 | doi-access = free }} Actin homologs from prokaryotes and archaea polymerize into different helical or linear filaments consisting of one or multiple strands. However the in-strand contacts and nucleotide binding sites are preserved in prokaryotes and in archaea.{{cite journal | vauthors = Ghoshdastider U, Jiang S, Popp D, Robinson RC | title = In search of the primordial actin filament | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 112 | issue = 30 | pages = 9150–9151 | date = Jul 2015 | pmid = 26178194 | pmc = 4522752 | doi = 10.1073/pnas.1511568112 | doi-access = free }} Lastly, actin plays an important role in the control of [[gene expression]]. [25] => [26] => A large number of [[disease|illnesses and diseases]] are caused by [[mutation]]s in [[allele]]s of the [[gene]]s that regulate the production of actin or of its associated proteins. The production of actin is also key to the process of [[infection]] by some [[pathogen]]ic [[microorganism]]s. Mutations in the different genes that regulate actin production in humans can cause [[Myopathy|muscular diseases]], variations in the size and function of the [[heart]] as well as [[deafness]]. The make-up of the cytoskeleton is also related to the pathogenicity of intracellular [[bacteria]] and [[virus]]es, particularly in the processes related to evading the actions of the [[immune system]].{{cite book | vauthors = Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P | title = Molecular biology of the cell | chapter-url = https://archive.org/details/molecularbiolog000wils | chapter-url-access = registration | publisher = Garland Science | location = New York | year = 2002 | pages = 907–982| isbn = 978-0-8153-3218-3 | chapter = Chapter 16: The cytoskeleton }} [27] => [28] => == Function == [29] => Actin's primary role in the cell is to form linear polymers called [[microfilament]]s that serve various functions in the cell's structure, trafficking networks, migration, and replication.{{sfn|Lodish|Berk|Kaiser|Krieger|2016|p=778}} The multifaceted role of actin relies on a few of the microfilaments' properties: First, the formation of actin filaments is reversible, and their function often involves undergoing rapid polymerization and depolymerization. Second, microfilaments are polarized – i.e. the two ends of a filament are distinct from one another. Third, actin filaments can bind to many other proteins, which together help modify and organize microfilaments for their diverse functions.{{sfn|Lodish|Berk|Kaiser|Krieger|2016|p=778}} [30] => [31] => In most cells actin filaments form larger-scale networks which are essential for many key functions:{{cite journal | vauthors = Huber F, Schnauß J, Rönicke S, Rauch P, Müller K, Fütterer C, Käs J | title = Emergent complexity of the cytoskeleton: from single filaments to tissue | journal = Advances in Physics | volume = 62 | issue = 1 | pages = 1–112 | date = January 2013 | pmid = 24748680 | pmc = 3985726 | doi = 10.1080/00018732.2013.771509 | bibcode = 2013AdPhy..62....1H }} [32] => * Actin networks give mechanical support to cells and provide trafficking routes through the cytoplasm to aid signal transduction. [33] => * Rapid assembly and disassembly of actin network enables cells to migrate ([[Cell migration]]). [34] => [35] => Actin is extremely abundant in most cells, comprising 1–5% of the total protein mass of most cells, and 10% of muscle cells.{{sfn|Lodish|Berk|Kaiser|Krieger|2016|p=778}} [36] => [37] => The actin protein is found in both the [[cytoplasm]] and the [[cell nucleus]]. Its location is regulated by cell membrane [[signal transduction]] pathways that integrate the stimuli that a cell receives stimulating the restructuring of the actin networks in response.{{cite book | vauthors = Eckert R, Randall D, Burggren WW, French K | title = Eckert animal physiology: mechanisms and adaptations | publisher = W.H. Freeman and CO | location = New York | year = 2002 | isbn = 978-0-7167-3863-3 | url = https://archive.org/details/eckertanimalphys00rand }} [38] => [39] => === Cytoskeleton === [40] => [[File:MEF microfilaments.jpg|thumb|[[Fluorescence microscope|Fluorescence]] micrograph showing F-actin (in green) in rat [[fibroblast]]s]] [41] => [42] => There are a number of different types of actin with slightly different structures and functions. α-actin is found exclusively in [[muscle fibre]]s, while β- and γ-actin are found in other cells. As the latter types have a high turnover rate the majority of them are found outside permanent structures. Microfilaments found in cells other than muscle cells are present in three forms: [43] => * '''Microfilament networks''' - [[Animal cell]]s commonly have a cell cortex under the [[cell membrane]] that contains a large number of microfilaments, which precludes the presence of [[organelle]]s. This network is connected with numerous [[Receptor (biochemistry)|receptor]]s that [[signal transduction|relay signals]] to the outside of a cell. [44] => [45] => [[File:STD Depth Coded Stack Phallodin Stained Actin Filaments.png|thumb|A merged stack of confocal images showing actin filaments within a cell. The image has been colour coded in the z axis to show in a 2D image which heights filaments can be found at within cells.]] [46] => * '''Periodic actin rings''' - A periodic structure constructed of evenly spaced actin rings is found in [[axon]]s.{{cite journal | vauthors = Xu K, Zhong G, Zhuang X | title = Actin, spectrin, and associated proteins form a periodic cytoskeletal structure in axons | journal = Science | volume = 339 | issue = 6118 | pages = 452–456 | date = Jan 2013 | pmid = 23239625 | pmc = 3815867 | doi = 10.1126/science.1232251 | bibcode = 2013Sci...339..452X }} In this structure, the actin rings, together with [[spectrin]] tetramers that link the neighboring actin rings, form a cohesive [[cytoskeleton]] that supports the axon membrane. The structure periodicity may also regulate the [[sodium ion channel]]s in axons. [47] => [48] => ==== Yeasts ==== [49] => Actin's cytoskeleton is key to the processes of [[endocytosis]], [[cytokinesis]], determination of [[cell polarity]] and [[morphogenesis]] in [[yeast]]s. In addition to relying on actin, these processes involve 20 or 30 associated proteins, which all have a high degree of evolutionary conservation, along with many signalling molecules. Together these elements allow a spatially and temporally modulated assembly that defines a cell's response to both internal and external stimuli.{{cite journal | vauthors = Moseley JB, Goode BL | title = The yeast actin cytoskeleton: from cellular function to biochemical mechanism | journal = Microbiology and Molecular Biology Reviews | volume = 70 | issue = 3 | pages = 605–645 | date = Sep 2006 | pmid = 16959963 | pmc = 1594590 | doi = 10.1128/MMBR.00013-06 }} [50] => [51] => Yeasts contain three main elements that are associated with actin: patches, cables, and rings. Despite not being present for long, these structures are subject to a dynamic equilibrium due to continual polymerization and depolymerization. They possess a number of accessory proteins including ADF/cofilin, which has a molecular weight of 16kDa and is coded for by a single gene, called ''COF1''; Aip1, a cofilin cofactor that promotes the disassembly of microfilaments; Srv2/CAP, a process regulator related to [[adenylate cyclase]] proteins; a profilin with a molecular weight of approximately 14 kDa that is related/associated with actin monomers; and twinfilin, a 40 kDa protein involved in the organization of patches. [52] => [53] => ==== Plants ==== [54] => Plant [[genome]] studies have revealed the existence of protein isovariants within the actin family of genes. Within ''[[Arabidopsis thaliana]]'', a [[model organism]], there are ten types of actin, six profilins, and dozens of myosins. This diversity is explained by the evolutionary necessity of possessing variants that slightly differ in their temporal and spatial expression. The majority of these proteins were jointly expressed in the [[Tissue (biology)|tissue]] analysed. Actin networks are distributed throughout the cytoplasm of cells that have been cultivated ''[[in vitro]]''. There is a concentration of the network around the nucleus that is connected via spokes to the cellular cortex, this network is highly dynamic, with a continuous polymerization and depolymerization.{{cite journal | vauthors = Meagher RB, McKinney EC, Kandasamy MK | title = Isovariant dynamics expand and buffer the responses of complex systems: the diverse plant actin gene family | journal = The Plant Cell | volume = 11 | issue = 6 | pages = 995–1006 | date = Jun 1999 | pmid = 10368172 | pmc = 1464670 | doi = 10.1105/tpc.11.6.995 }} [55] => [56] => [[File:PDB 1unc EBI.jpg|thumb|left|[[Protein structure|Structure]] of the C-terminal subdomain of [[villin]], a protein capable of splitting microfilaments[[Protein Data Bank|PDB]] {{PDBe|1unc}}; {{cite journal | vauthors = Vermeulen W, Vanhaesebrouck P, Van Troys M, Verschueren M, Fant F, Goethals M, Ampe C, Martins JC, Borremans FA | title = Solution structures of the C-terminal headpiece subdomains of human villin and advillin, evaluation of headpiece F-actin-binding requirements | journal = Protein Science | volume = 13 | issue = 5 | pages = 1276–1287 | date = May 2004 | pmid = 15096633 | pmc = 2286768 | doi = 10.1110/ps.03518104 }}]] [57] => [58] => Even though the majority of plant cells have a [[Plant cell wall|cell wall]] that defines their morphology, their microfilaments can generate sufficient force to achieve a number of cellular activities, such as the cytoplasmic currents generated by the microfilaments and myosin. Actin is also involved in the movement of organelles and in cellular morphogenesis, which involve [[cell division]] as well as the elongation and differentiation of the cell.{{cite journal | vauthors = Higaki T, Sano T, Hasezawa S | title = Actin microfilament dynamics and actin side-binding proteins in plants | journal = Current Opinion in Plant Biology | volume = 10 | issue = 6 | pages = 549–556 | date = Dec 2007 | pmid = 17936064 | doi = 10.1016/j.pbi.2007.08.012 }} [59] => [60] => The most notable proteins associated with the actin cytoskeleton in plants include: [[villin]], which belongs to the same family as [[gelsolin]]/severin and is able to cut microfilaments and bind actin monomers in the presence of calcium cations; [[fimbrin]], which is able to recognize and unite actin monomers and which is involved in the formation of networks (by a different regulation process from that of animals and yeasts);{{cite journal | vauthors = Kovar DR, Staiger CJ, Weaver EA, McCurdy DW | title = AtFim1 is an actin filament crosslinking protein from Arabidopsis thaliana | journal = The Plant Journal | volume = 24 | issue = 5 | pages = 625–636 | date = Dec 2000 | pmid = 11123801 | doi = 10.1046/j.1365-313x.2000.00907.x | doi-access = free }} [[formin]]s, which are able to act as an F-actin polymerization nucleating agent; [[myosin]], a typical molecular motor that is specific to eukaryotes and which in ''Arabidopsis thaliana'' is coded for by 17 genes in two distinct classes; CHUP1, which can bind actin and is implicated in the spatial distribution of [[chloroplast]]s in the cell; KAM1/MUR3 that define the morphology of the [[Golgi apparatus]] as well as the composition of [[xyloglucan]]s in the cell wall; NtWLIM1, which facilitates the emergence of actin cell structures; and ERD10, which is involved in the association of organelles within [[cell membrane|membranes]] and microfilaments and which seems to play a role that is involved in an organism's reaction to [[Stress (biology)|stress]]. [61] => [62] => === Nuclear actin === [63] => Nuclear actin was first noticed and described in 1977 by Clark and Merriam.{{cite journal | vauthors = Clark TG, Merriam RW | title = Diffusible and bound actin nuclei of Xenopus laevis oocytes | journal = Cell | volume = 12 | issue = 4 | pages = 883–891 | date = Dec 1977 | pmid = 563771 | doi = 10.1016/0092-8674(77)90152-0 | s2cid = 34708250 }} Authors describe a protein present in the nuclear fraction, obtained from ''Xenopus laevis'' oocytes, which shows the same features as skeletal muscle actin. Since that time there have been many scientific reports about the structure and functions of actin in the nucleus (for review see: Hofmann 2009.{{Cite book | vauthors = Hofmann WA | title = Cell and molecular biology of nuclear actin | volume = 273 | pages = 219–263 | date = 2009-01-01 | pmid = 19215906 | doi = 10.1016/S1937-6448(08)01806-6 | series = International Review of Cell and Molecular Biology | isbn = 9780123748041 }}) The controlled level of actin in the nucleus, its interaction with actin-binding proteins (ABP) and the presence of different isoforms allows actin to play an important role in many important nuclear processes.{{cite journal | vauthors = Ulferts S, Prajapati B, Grosse R, Vartiainen MK | title = Emerging properties and functions of actin and actin filaments inside the nucleus | journal = Cold Spring Harbor Perspectives in Biology | volume = 13 | issue = 3 | pages = a040121 | date = Feb 2021 | pmid = 33288541 | pmc = 7919393 | doi = 10.1101/cshperspect.a040121 }} [64] => [65] => ==== Transport through the nuclear membrane ==== [66] => The actin sequence does not contain a nuclear localization signal. The small size of actin (about 43 kDa) allows it to enter the nucleus by passive diffusion.{{cite journal | vauthors = Bohnsack MT, Stüven T, Kuhn C, Cordes VC, Görlich D | title = A selective block of nuclear actin export stabilizes the giant nuclei of Xenopus oocytes | journal = Nature Cell Biology | volume = 8 | issue = 3 | pages = 257–263 | date = Mar 2006 | pmid = 16489345 | doi = 10.1038/ncb1357 | hdl = 11858/00-001M-0000-0012-E6EB-9 | s2cid = 16529470 | hdl-access = free }} The import of actin into the nucleus (probably in a complex with cofilin) is facilitated by the import protein importin 9.{{cite journal | vauthors = Dopie J, Skarp KP, Rajakylä EK, Tanhuanpää K, Vartiainen MK | title = Active maintenance of nuclear actin by importin 9 supports transcription | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 109 | issue = 9 | pages = E544–552 | date = Feb 2012 | pmid = 22323606 | pmc = 3295300 | doi = 10.1073/pnas.1118880109 | doi-access = free }} [67] => [68] => Low levels of actin in the nucleus seems to be important, because actin has two nuclear export signals (NES) in its sequence. Microinjected actin is quickly removed from the nucleus to the cytoplasm. Actin is exported at least in two ways, through [[XPO1|exportin 1]] and [[XPO6|exportin 6]].{{cite journal | vauthors = Wada A, Fukuda M, Mishima M, Nishida E | title = Nuclear export of actin: a novel mechanism regulating the subcellular localization of a major cytoskeletal protein | journal = The EMBO Journal | volume = 17 | issue = 6 | pages = 1635–1641 | date = Mar 1998 | pmid = 9501085 | pmc = 1170511 | doi = 10.1093/emboj/17.6.1635 }}{{cite journal | vauthors = Stüven T, Hartmann E, Görlich D | title = Exportin 6: a novel nuclear export receptor that is specific for profilin.actin complexes | journal = The EMBO Journal | volume = 22 | issue = 21 | pages = 5928–5940 | date = Nov 2003 | pmid = 14592989 | pmc = 275422 | doi = 10.1093/emboj/cdg565 }} Specific modifications, such as SUMOylation, allows for nuclear actin retention. A mutation preventing SUMOylation causes rapid export of beta actin from the nucleus.{{cite journal | vauthors = Hofmann WA, Arduini A, Nicol SM, Camacho CJ, Lessard JL, Fuller-Pace FV, de Lanerolle P | title = SUMOylation of nuclear actin | journal = The Journal of Cell Biology | volume = 186 | issue = 2 | pages = 193–200 | date = Jul 2009 | pmid = 19635839 | pmc = 2717643 | doi = 10.1083/jcb.200905016 }} [69] => [70] => ==== Organization ==== [71] => Nuclear actin exists mainly as a monomer, but can also form dynamic oligomers and short polymers.{{cite journal | vauthors = McDonald D, Carrero G, Andrin C, de Vries G, Hendzel MJ | title = Nucleoplasmic beta-actin exists in a dynamic equilibrium between low-mobility polymeric species and rapidly diffusing populations | journal = The Journal of Cell Biology | volume = 172 | issue = 4 | pages = 541–552 | date = Feb 2006 | pmid = 16476775 | pmc = 2063674 | doi = 10.1083/jcb.200507101 }}{{cite journal | vauthors = Jockusch BM, Schoenenberger CA, Stetefeld J, Aebi U | title = Tracking down the different forms of nuclear actin | journal = Trends in Cell Biology | volume = 16 | issue = 8 | pages = 391–396 | date = Aug 2006 | pmid = 16828286 | doi = 10.1016/j.tcb.2006.06.006 }}{{cite journal | vauthors = Migocka-Patrzałek M, Makowiecka A, Nowak D, Mazur AJ, Hofmann WA, Malicka-Błaszkiewicz M | title = β- and γ-Actins in the nucleus of human melanoma A375 cells | journal = Histochemistry and Cell Biology | volume = 144 | issue = 5 | pages = 417–428 | date = Nov 2015 | pmid = 26239425 | pmc = 4628621 | doi = 10.1007/s00418-015-1349-8 }} Nuclear actin organization varies in different cell types. For example, in ''Xenopus'' oocytes (with higher nuclear actin level in comparison to somatic cells) actin forms filaments, which stabilize nucleus architecture. These filaments can be observed under the microscope thanks to fluorophore-conjugated phalloidin staining. [72] => [73] => In somatic cell nuclei, however, actin filaments cannot be observed using this technique.{{cite journal | vauthors = Pederson T, Aebi U | title = Actin in the nucleus: what form and what for? | journal = Journal of Structural Biology | volume = 140 | issue = 1–3 | pages = 3–9 | date = 2002-12-01 | pmid = 12490148 | doi=10.1016/s1047-8477(02)00528-2}} The DNase I inhibition assay, the only test which allows the quantification of the polymerized actin directly in biological samples, has revealed that endogenous nuclear actin indeed occurs mainly in a monomeric form. [74] => [75] => Precisely controlled level of actin in the cell nucleus, lower than in the cytoplasm, prevents the formation of filaments. The polymerization is also reduced by the limited access to actin monomers, which are bound in complexes with ABPs, mainly cofilin.{{cite journal | vauthors = Chhabra D, dos Remedios CG | title = Cofilin, actin and their complex observed in vivo using fluorescence resonance energy transfer | journal = Biophysical Journal | volume = 89 | issue = 3 | pages = 1902–1908 | date = Sep 2005 | pmid = 15994898 | pmc = 1366693 | doi = 10.1529/biophysj.105.062083 | bibcode = 2005BpJ....89.1902C }} [76] => [77] => ==== Actin isoforms ==== [78] => Different isoforms of actin are present in the cell nucleus. The level of actin isoforms may change in response to stimulation of cell growth or arrest of proliferation and transcriptional activity.{{cite journal | vauthors = Spencer VA | title = Nuclear actin: A key player in extracellular matrix-nucleus communication | journal = Communicative & Integrative Biology | volume = 4 | issue = 5 | pages = 511–512 | date = Sep 2011 | pmid = 22046450 | pmc = 3204115 | doi = 10.4161/cib.16256 }} Research on nuclear actin is focused on isoform beta.{{cite journal | vauthors = Zhao K, Wang W, Rando OJ, Xue Y, Swiderek K, Kuo A, Crabtree GR | title = Rapid and phosphoinositol-dependent binding of the SWI/SNF-like BAF complex to chromatin after T lymphocyte receptor signaling | journal = Cell | volume = 95 | issue = 5 | pages = 625–636 | date = Nov 1998 | pmid = 9845365 | doi = 10.1016/s0092-8674(00)81633-5| s2cid = 3184211 | doi-access = free }}{{cite journal | vauthors = Hofmann WA, Stojiljkovic L, Fuchsova B, Vargas GM, Mavrommatis E, Philimonenko V, Kysela K, Goodrich JA, Lessard JL, Hope TJ, Hozak P, de Lanerolle P | title = Actin is part of pre-initiation complexes and is necessary for transcription by RNA polymerase II | journal = Nature Cell Biology | volume = 6 | issue = 11 | pages = 1094–1101 | date = Nov 2004 | pmid = 15502823 | doi = 10.1038/ncb1182 | s2cid = 23909479 }}{{cite journal | vauthors = Hu P, Wu S, Hernandez N | title = A role for beta-actin in RNA polymerase III transcription | journal = Genes & Development | volume = 18 | issue = 24 | pages = 3010–3015 | date = Dec 2004 | pmid = 15574586 | pmc = 535912 | doi = 10.1101/gad.1250804 }}{{cite journal | vauthors = Philimonenko VV, Zhao J, Iben S, Dingová H, Kyselá K, Kahle M, Zentgraf H, Hofmann WA, de Lanerolle P, Hozák P, Grummt I | title = Nuclear actin and myosin I are required for RNA polymerase I transcription | journal = Nature Cell Biology | volume = 6 | issue = 12 | pages = 1165–1172 | date = Dec 2004 | pmid = 15558034 | doi = 10.1038/ncb1190 | s2cid = 6633625 }} However the use of antibodies directed against different actin isoforms allows identifying not only the cytoplasmic beta in the cell nucleus, but also alpha- and gamma-actin in certain cell types.{{cite journal | vauthors = Maraldi NM, Lattanzi G, Marmiroli S, Squarzoni S, Manzoli FA | title = New roles for lamins, nuclear envelope proteins and actin in the nucleus | journal = Advances in Enzyme Regulation | volume = 44 | pages = 155–172 | date = 2004-01-01 | pmid = 15581488 | doi = 10.1016/j.advenzreg.2003.11.005 }}{{cite journal | vauthors = Tondeleir D, Lambrechts A, Müller M, Jonckheere V, Doll T, Vandamme D, Bakkali K, Waterschoot D, Lemaistre M, Debeir O, Decaestecker C, Hinz B, Staes A, Timmerman E, Colaert N, Gevaert K, Vandekerckhove J, Ampe C | title = Cells lacking β-actin are genetically reprogrammed and maintain conditional migratory capacity | journal = Molecular & Cellular Proteomics | volume = 11 | issue = 8 | pages = 255–271 | date = Aug 2012 | pmid = 22448045 | pmc = 3412960 | doi = 10.1074/mcp.M111.015099 |doi-access=free }} The presence of different isoforms of actin may have a significant effect on its function in nuclear processes, as the level of individual isoforms can be controlled independently. [79] => [80] => ==== Functions ==== [81] => Functions of actin in the nucleus are associated with its ability to polymerize and interact with various ABPs and with structural elements of the nucleus. Nuclear actin is involved in: [82] => * '''Architecture of the nucleus''' - Interaction of actin with alpha II-spectrin and other proteins are important for maintaining proper shape of the nucleus.{{cite journal | vauthors = Holaska JM, Kowalski AK, Wilson KL | title = Emerin caps the pointed end of actin filaments: evidence for an actin cortical network at the nuclear inner membrane | journal = PLOS Biology | volume = 2 | issue = 9 | pages = E231 | date = Sep 2004 | pmid = 15328537 | pmc = 509406 | doi = 10.1371/journal.pbio.0020231 | doi-access = free }}{{Cite book | vauthors = Puckelwartz M, McNally EM | volume = 101 | pages = 155–166 | date = 2011-01-01 | pmid = 21496632 | doi = 10.1016/B978-0-08-045031-5.00012-8 | series = Handbook of Clinical Neurology | isbn = 9780080450315 | title = Muscular Dystrophies | chapter = Emery–Dreifuss muscular dystrophy }} [83] => * '''Transcription''' – Actin is involved in chromatin reorganization,{{cite journal | vauthors = Farrants AK | title = Chromatin remodelling and actin organisation | journal = FEBS Letters | volume = 582 | issue = 14 | pages = 2041–2050 | date = Jun 2008 | pmid = 18442483 | doi = 10.1016/j.febslet.2008.04.032 | s2cid = 23147656 | doi-access = free }}{{cite journal | vauthors = Sjölinder M, Björk P, Söderberg E, Sabri N, Farrants AK, Visa N | title = The growing pre-mRNA recruits actin and chromatin-modifying factors to transcriptionally active genes | journal = Genes & Development | volume = 19 | issue = 16 | pages = 1871–1884 | date = Aug 2005 | pmid = 16103215 | pmc = 1186187 | doi = 10.1101/gad.339405 }} transcription initiation and interaction with the transcription complex.{{cite journal | vauthors = Percipalle P, Visa N | title = Molecular functions of nuclear actin in transcription | journal = The Journal of Cell Biology | volume = 172 | issue = 7 | pages = 967–971 | date = Mar 2006 | pmid = 16549500 | pmc = 2063754 | doi = 10.1083/jcb.200512083 }} Actin takes part in the regulation of chromatin structure,{{cite journal | vauthors = Fedorova E, Zink D | title = Nuclear architecture and gene regulation | journal = Biochimica et Biophysica Acta (BBA) - Molecular Cell Research | volume = 1783 | issue = 11 | pages = 2174–2184 | date = Nov 2008 | pmid = 18718493 | doi = 10.1016/j.bbamcr.2008.07.018 | doi-access = free }}{{cite journal | vauthors = Skarp KP, Vartiainen MK | title = Actin on DNA-an ancient and dynamic relationship | journal = Cytoskeleton | volume = 67 | issue = 8 | pages = 487–495 | date = Aug 2010 | pmid = 20593452 | doi = 10.1002/cm.20464 | s2cid = 37763449 | doi-access = free }}{{cite journal | vauthors = Olave IA, Reck-Peterson SL, Crabtree GR | title = Nuclear actin and actin-related proteins in chromatin remodeling | journal = Annual Review of Biochemistry | volume = 71 | pages = 755–781 | date = 2002-01-01 | pmid = 12045110 | doi = 10.1146/annurev.biochem.71.110601.135507 }} interacting with RNA polymerase I, II and III. In Pol I transcription, actin and myosin ([[MYO1C]], which binds DNA) act as a [[molecular motor]]. For Pol II transcription, β-actin is needed for the formation of the preinitiation complex. Pol III contains β-actin as a subunit. Actin can also be a component of chromatin remodelling complexes as well as pre-mRNP particles (that is, precursor [[messenger RNA]] bundled in proteins), and is involved in [[nuclear pore|nuclear export]] of RNAs and proteins.{{cite journal | vauthors = Zheng B, Han M, Bernier M, Wen JK | title = Nuclear actin and actin-binding proteins in the regulation of transcription and gene expression | journal = The FEBS Journal | volume = 276 | issue = 10 | pages = 2669–2685 | date = May 2009 | pmid = 19459931 | pmc = 2978034 | doi = 10.1111/j.1742-4658.2009.06986.x }} [84] => * '''Regulation of gene activity''' – Actin binds to the regulatory regions of different kinds of genes.{{cite journal | vauthors = Ferrai C, Naum-Onganía G, Longobardi E, Palazzolo M, Disanza A, Diaz VM, Crippa MP, Scita G, Blasi F | title = Induction of HoxB transcription by retinoic acid requires actin polymerization | journal = Molecular Biology of the Cell | volume = 20 | issue = 15 | pages = 3543–3551 | date = Aug 2009 | pmid = 19477923 | pmc = 2719572 | doi = 10.1091/mbc.E09-02-0114 }}{{cite journal | vauthors = Xu YZ, Thuraisingam T, Morais DA, Rola-Pleszczynski M, Radzioch D | title = Nuclear translocation of beta-actin is involved in transcriptional regulation during macrophage differentiation of HL-60 cells | journal = Molecular Biology of the Cell | volume = 21 | issue = 5 | pages = 811–820 | date = Mar 2010 | pmid = 20053683 | pmc = 2828967 | doi = 10.1091/mbc.E09-06-0534 }}{{cite journal | vauthors = Miyamoto K, Pasque V, Jullien J, Gurdon JB | title = Nuclear actin polymerization is required for transcriptional reprogramming of Oct4 by oocytes | journal = Genes & Development | volume = 25 | issue = 9 | pages = 946–958 | date = May 2011 | pmid = 21536734 | pmc = 3084028 | doi = 10.1101/gad.615211 }}{{cite journal | vauthors = Huang W, Ghisletti S, Saijo K, Gandhi M, Aouadi M, Tesz GJ, Zhang DX, Yao J, Czech MP, Goode BL, Rosenfeld MG, Glass CK | title = Coronin 2A mediates actin-dependent de-repression of inflammatory response genes | journal = Nature | volume = 470 | issue = 7334 | pages = 414–418 | date = Feb 2011 | pmid = 21331046 | pmc = 3464905 | doi = 10.1038/nature09703 | bibcode = 2011Natur.470..414H }} Actin's ability to regulate gene activity is used in the molecular reprogramming method, which allows differentiated cells return to their embryonic state.{{cite journal | vauthors = Miyamoto K, Gurdon JB | title = Nuclear actin and transcriptional activation | journal = Communicative & Integrative Biology | volume = 4 | issue = 5 | pages = 582–583 | date = Sep 2011 | pmid = 22046469 | pmc = 3204135 | doi = 10.4161/cib.16491 }} [85] => * '''Translocation of the activated chromosome fragment''' from under membrane region to euchromatin where transcription starts. This movement requires the interaction of actin and myosin.{{cite journal | vauthors = Chuang CH, Carpenter AE, Fuchsova B, Johnson T, de Lanerolle P, Belmont AS | title = Long-range directional movement of an interphase chromosome site | journal = Current Biology | volume = 16 | issue = 8 | pages = 825–831 | date = Apr 2006 | pmid = 16631592 | doi = 10.1016/j.cub.2006.03.059 | s2cid = 1191289 | doi-access = free }}{{cite journal | vauthors = Hofmann WA, Vargas GM, Ramchandran R, Stojiljkovic L, Goodrich JA, de Lanerolle P | title = Nuclear myosin I is necessary for the formation of the first phosphodiester bond during transcription initiation by RNA polymerase II | journal = Journal of Cellular Biochemistry | volume = 99 | issue = 4 | pages = 1001–1009 | date = Nov 2006 | pmid = 16960872 | doi = 10.1002/jcb.21035 | s2cid = 39237955 }} [86] => * '''Integration of different cellular compartments'''. Actin is a molecule that integrates cytoplasmic and nuclear signal transduction pathways.{{cite journal | vauthors = Olson EN, Nordheim A | title = Linking actin dynamics and gene transcription to drive cellular motile functions | journal = Nature Reviews Molecular Cell Biology | volume = 11 | issue = 5 | pages = 353–365 | date = May 2010 | pmid = 20414257 | pmc = 3073350 | doi = 10.1038/nrm2890 }} An example is the activation of transcription in response to serum stimulation of cells ''in vitro''.{{cite journal | vauthors = Miralles F, Posern G, Zaromytidou AI, Treisman R | title = Actin dynamics control SRF activity by regulation of its coactivator MAL | journal = Cell | volume = 113 | issue = 3 | pages = 329–342 | date = May 2003 | pmid = 12732141 | doi=10.1016/s0092-8674(03)00278-2| citeseerx = 10.1.1.327.7451 | s2cid = 17209744 }}{{cite journal | vauthors = Vartiainen MK | title = Nuclear actin dynamics--from form to function | journal = FEBS Letters | volume = 582 | issue = 14 | pages = 2033–2040 | date = Jun 2008 | pmid = 18423404 | doi = 10.1016/j.febslet.2008.04.010 | s2cid = 35474838 }}{{cite journal | vauthors = Knöll B | title = Actin-mediated gene expression in neurons: the MRTF-SRF connection | journal = Biological Chemistry | volume = 391 | issue = 6 | pages = 591–597 | date = Jun 2010 | pmid = 20370316 | doi = 10.1515/BC.2010.061 | s2cid = 36373214 }} [87] => * '''Immune response''' - Nuclear actin polymerizes upon [[T-cell receptor]] stimulation and is required for cytokine expression and antibody production ''in vivo''.{{cite journal | vauthors = Tsopoulidis N, Kaw S, Laketa V, Kutscheidt S, Baarlink C, Stolp B, Grosse R, Fackler OT | title = T cell receptor-triggered nuclear actin network formation drives CD4+ T cell effector functions| journal = Science Immunology | volume = 4 | issue = 31 | pages = eaav1987| date = Jan 2019 | pmid = 30610013 | doi=10.1126/sciimmunol.aav1987| doi-access = free }} [88] => * '''DNA repair''' - Nuclear actin mediates the repair of [[DNA damage (naturally occurring)|DNA double-strand breaks]].Huang Y, Zhang S, Park JI. Nuclear Actin Dynamics in Gene Expression, DNA Repair, and Cancer. Results Probl Cell Differ. 2022;70:625-663. doi: 10.1007/978-3-031-06573-6_23. {{PMID|36348125}}; PMCID: PMC9677682 In the [[cell nucleus]], a filamentous polymer of actin (F-actin) acts both in the DNA repair pathway of non homologous end joining and in the pathway of [[homology directed repair|homologous recombinational repair]]. [89] => [90] => Due to its ability to undergo conformational changes and interaction with many proteins, actin acts as a regulator of formation and activity of protein complexes such as transcriptional complex. [91] => [92] => === Cell movement === [93] => Actin is also involved in cell movement. A meshwork of actin filaments marks the forward edge of a moving cell, and the polymerization of new actin filaments pushes the cell membrane forward in protrusions called [[lamellipodium|lamellipodia]].{{sfn|Lodish|Berk|Kaiser|Krieger|2016|p=811–812}} These membrane protrusions then attach to the substrate, forming structures known as [[focal adhesions]] that connect to the actin network.{{sfn|Lodish|Berk|Kaiser|Krieger|2016|p=811–812}} Once attached, the rear of the cell body contracts squeezing its contents forward past the adhesion point.{{sfn|Lodish|Berk|Kaiser|Krieger|2016|p=811–812}} Once the adhesion point has moved to the rear of the cell, the cell disassembles it, allowing the rear of the cell to move forward.{{sfn|Lodish|Berk|Kaiser|Krieger|2016|p=811–812}} [94] => [[File:Cardiac sarcomere structure.png|thumb|285x285px|Cardiac sarcomere structure featuring actin and myosin]] [95] => [96] => === Actin/myosin movement === [97] => [98] => In addition to the physical force generated by actin polymerization, microfilaments facilitate the movement of various intracellular components by serving as the roadway along which a family of [[motor protein]]s called [[myosin]]s travel.{{sfn|Lodish|Berk|Kaiser|Krieger|2016|p=796}} [99] => [100] => ==== Muscle contraction ==== [101] => {{Main|Muscle contraction}} [102] => [[File:Sarcomere.svg|thumb|The structure of a [[sarcomere]], the basic morphological and functional unit of the skeletal muscles that contains actin|291x291px]] [103] => [104] => Actin plays a particularly prominent role in muscle cells, which consist largely of repeated bundles of actin and [[myosin II]].{{sfn|Lodish|Berk|Kaiser|Krieger|2016|p=803–805}} Each repeated unit – called a [[sarcomere]] – consists of two sets of oppositely oriented F-actin strands ("thin filaments"), interlaced with bundles of myosin ("thick filaments"). The two sets of actin strands are oriented with their (+) ends embedded in either end of the sarcomere in delimiting structures called [[Z-disk]]s.{{sfn|Lodish|Berk|Kaiser|Krieger|2016|p=803–805}} The myosin fibrils are in the middle between the sets of actin filaments, with strands facing in both directions. When the muscle contracts, the myosin threads move along the actin filaments towards the (+) end, pulling the ends of the sarcomere together and shortening it by around 70% of its length.{{sfn|Lodish|Berk|Kaiser|Krieger|2016|p=803–805}} In order to move along the actin thread, myosin must hydrolyze ATP; thus ATP serves as the energy source for muscle contraction.{{sfn|Lodish|Berk|Kaiser|Krieger|2016|p=803–805}} [105] => [106] => At times of rest, the proteins [[tropomyosin]] and [[troponin]] bind to the actin filaments, preventing the attachment of myosin.{{sfn|Lodish|Berk|Kaiser|Krieger|2016|p=803–805}} When an activation signal (i.e. an [[action potential]]) arrives at the muscle fiber, it triggers the release of Ca2+ from the [[sarcoplasmic reticulum]] into the cytosol. The resulting spike in cytosolic calcium rapidly releases tropomyosin and troponin from the actin thread, allowing myosin to bind, and muscle contracation to begin.{{sfn|Lodish|Berk|Kaiser|Krieger|2016|p=805–806}} [107] => [108] => ====Cell division==== [109] => In the final stages of [[cell division]], many cells form a ring of actin at the cell's midpoint. This ring, aptly called the "[[contractile ring]]", uses a similar mechanism as muscle fibers where myosin II pulls along the actin ring, causing it to contract.{{sfn|Lodish|Berk|Kaiser|Krieger|2016|p=807}} This contraction cleaves the parent cell into two, completing [[cytokinesis]].{{sfn|Lodish|Berk|Kaiser|Krieger|2016|p=807}} The contractile ring is composed of actin, myosin, [[anillin]], and [[actinin|α-actinin]].{{cite journal | vauthors = Fujiwara K, Porter ME, Pollard TD | title = Alpha-actinin localization in the cleavage furrow during cytokinesis | journal = The Journal of Cell Biology | volume = 79 | issue = 1 | pages = 268–275 | date = Oct 1978 | pmid = 359574 | pmc = 2110217 | doi = 10.1083/jcb.79.1.268 }} In the fission yeast ''[[Schizosaccharomyces pombe]]'', actin is actively formed in the constricting ring with the participation of [[Arp2/3|Arp3]], the [[formin]] Cdc12, [[profilin]], and [[WASp]], along with preformed microfilaments. Once the ring has been constructed the structure is maintained by a continual assembly and disassembly that, aided by the [[Arp2/3]] complex and formins, is key to one of the central processes of cytokinesis.{{cite journal | vauthors = Pelham RJ, Chang F | title = Actin dynamics in the contractile ring during cytokinesis in fission yeast | journal = Nature | volume = 419 | issue = 6902 | pages = 82–86 | date = Sep 2002 | pmid = 12214236 | doi = 10.1038/nature00999 | bibcode = 2002Natur.419...82P | s2cid = 4389564 }} [110] => [111] => ====Intracellular trafficking==== [112] => Actin-myosin pairs can also participate in the trafficking of various [[membrane vesicle]]s and [[organelle]]s within the cell. [[Myosin V]] is activated by binding to various cargo receptors on organelles, and then moves along an actin filament towards the (+) end, pulling its cargo along with it.{{sfn|Lodish|Berk|Kaiser|Krieger|2016|p=809}} [113] => [114] => These nonconventional myosins use ATP hydrolysis to transport cargo, such as [[Vesicle (biology)|vesicles]] and organelles, in a directed fashion much faster than diffusion. Myosin V walks towards the barbed end of actin filaments, while myosin VI walks toward the pointed end. Most actin filaments are arranged with the barbed end toward the cellular membrane and the pointed end toward the cellular interior. This arrangement allows myosin V to be an effective motor for the export of cargos, and myosin VI to be an effective motor for import. [115] => [116] => === Other biological processes === [117] => [[File:Diverse-roles-of-actin-in-C.-elegans-early-embryogenesis-1471-213X-7-142-S9.ogv|thumb|Fluorescence imaging of actin dynamics during the first embryonic cell division of ''C. elegans''. First, actin filaments assemble in the upper part of the cell, thus contributing to [[asymmetric cell division#Asymmetric cell division in C. elegans|asymmetric cell division]]. Then, at 10 s, formation of the contractile actin ring can be observed.]] [118] => [119] => The traditional image of actin's function relates it to the maintenance of the cytoskeleton and, therefore, the organization and movement of organelles, as well as the determination of a cell's shape.{{cite book| vauthors = Paniagua R, Nistal M, Sesma P, Álvarez-Uría M, Fraile B, Anadón R, José Sáez F | title = Citología e histología vegetal y animal | year = 2002 | publisher = McGraw-Hill Interamericana de España, S.A.U. | language = es| isbn = 978-84-486-0436-3}} However, actin has a wider role in eukaryotic cell physiology, in addition to similar functions in [[prokaryote]]s. [120] => * [[Apoptosis]]. During [[programmed cell death]] the ICE/ced-3 family of proteases (one of the interleukin-1β-converter proteases) degrade actin into two fragments ''in vivo''; one of the fragments is 15 kDa and the other 31 kDa. This represents one of the mechanisms involved in destroying cell viability that form the basis of apoptosis.{{cite journal | vauthors = Mashima T, Naito M, Noguchi K, Miller DK, Nicholson DW, Tsuruo T | title = Actin cleavage by CPP-32/apopain during the development of apoptosis | journal = Oncogene | volume = 14 | issue = 9 | pages = 1007–1012 | date = Mar 1997 | pmid = 9070648 | doi = 10.1038/sj.onc.1200919 | doi-access = free }} The protease [[calpain]] has also been shown to be involved in this type of cell destruction;{{cite journal | vauthors = Wang KK | title = Calpain and caspase: can you tell the difference? | journal = Trends in Neurosciences | volume = 23 | issue = 1 | pages = 20–26 | date = Jan 2000 | pmid = 10631785 | doi = 10.1016/S0166-2236(99)01479-4 | s2cid = 17571984 }} just as the use of calpain inhibitors has been shown to decrease actin proteolysis and the degradation of [[DNA]] (another of the characteristic elements of apoptosis).{{cite journal | vauthors = Villa PG, Henzel WJ, Sensenbrenner M, Henderson CE, Pettmann B | title = Calpain inhibitors, but not caspase inhibitors, prevent actin proteolysis and DNA fragmentation during apoptosis | journal = Journal of Cell Science | volume = 111 | issue = Pt 6 | pages = 713–722 | date = Mar 1998 | doi = 10.1242/jcs.111.6.713 | pmid = 9472000 }} On the other hand, the [[Stress (biology)|stress]]-induced triggering of apoptosis causes the reorganization of the actin cytoskeleton (which also involves its polymerization), giving rise to structures called [[stress fiber]]s; this is activated by the [[MAPK/ERK pathway|MAP kinase]] pathway.{{cite journal | vauthors = Huot J, Houle F, Rousseau S, Deschesnes RG, Shah GM, Landry J | title = SAPK2/p38-dependent F-actin reorganization regulates early membrane blebbing during stress-induced apoptosis | journal = The Journal of Cell Biology | volume = 143 | issue = 5 | pages = 1361–1373 | date = Nov 1998 | pmid = 9832563 | pmc = 2133090 | doi = 10.1083/jcb.143.5.1361 }} [121] => [122] => [[File:Cellular tight junction keys.svg|thumb|Diagram of a ''[[zonula occludens]]'' or tight junction, a structure that joins the [[epithelium]] of two cells. Actin is one of the anchoring elements shown in green.]] [123] => * [[Cellular adhesion]] and [[Developmental biology|development]]. The adhesion between cells is a characteristic of [[multicellular organisms]] that enables [[Tissue (biology)|tissue]] specialization and therefore increases cell complexity. Adhesion of cell [[epithelium|epithelia]] involves the actin cytoskeleton in each of the joined cells as well as [[cadherin]]s acting as extracellular elements with the connection between the two mediated by [[catenin]]s.{{cite journal | vauthors = Adams CL, Nelson WJ, Smith SJ | title = Quantitative analysis of cadherin-catenin-actin reorganization during development of cell-cell adhesion | journal = The Journal of Cell Biology | volume = 135 | issue = 6 Pt 2 | pages = 1899–1911 | date = Dec 1996 | pmid = 8991100 | pmc = 2133977 | doi = 10.1083/jcb.135.6.1899 }} Interfering in actin dynamics has repercussions for an organism's development, in fact actin is such a crucial element that systems of redundant [[gene]]s are available. For example, if the [[α-actinin]] or [[gelation]] factor gene has been removed in ''[[Dictyostelium]]'' individuals do not show an anomalous [[phenotype]] possibly due to the fact that each of the proteins can perform the function of the other. However, the development of [[Mutation|double mutations]] that lack both gene types is affected.{{cite journal | vauthors = Witke W, Schleicher M, Noegel AA | title = Redundancy in the microfilament system: abnormal development of Dictyostelium cells lacking two F-actin cross-linking proteins | journal = Cell | volume = 68 | issue = 1 | pages = 53–62 | date = Jan 1992 | pmid = 1732064 | doi = 10.1016/0092-8674(92)90205-Q | s2cid = 37569656 }} [124] => * [[Gene expression]] modulation. Actin's state of polymerization affects the pattern of [[gene expression]]. In 1997, it was discovered that cytocalasin D-mediated depolymerization in [[Schwann cell]]s causes a specific pattern of expression for the genes involved in the [[myelinization]] of this type of [[Neuron|nerve cell]].{{cite journal | vauthors = Fernandez-Valle C, Gorman D, Gomez AM, Bunge MB | title = Actin plays a role in both changes in cell shape and gene-expression associated with Schwann cell myelination | journal = The Journal of Neuroscience | volume = 17 | issue = 1 | pages = 241–250 | date = Jan 1997 | pmid = 8987752 | pmc = 6793673 | doi = 10.1523/JNEUROSCI.17-01-00241.1997}} F-actin has been shown to modify the [[transcriptome]] in some of the life stages of unicellular organisms, such as the fungus ''[[Candida albicans]]''.{{cite journal | vauthors = Wolyniak MJ, Sundstrom P | title = Role of actin cytoskeletal dynamics in activation of the cyclic AMP pathway and HWP1 gene expression in Candida albicans | journal = Eukaryotic Cell | volume = 6 | issue = 10 | pages = 1824–1840 | date = Oct 2007 | pmid = 17715368 | pmc = 2043390 | doi = 10.1128/EC.00188-07 }} In addition, proteins that are similar to actin play a regulatory role during [[spermatogenesis]] in [[Muridae|mice]]{{cite journal | vauthors = Tanaka H, Iguchi N, Egydio de Carvalho C, Tadokoro Y, Yomogida K, Nishimune Y | title = Novel actin-like proteins T-ACTIN 1 and T-ACTIN 2 are differentially expressed in the cytoplasm and nucleus of mouse haploid germ cells | journal = Biology of Reproduction | volume = 69 | issue = 2 | pages = 475–482 | date = Aug 2003 | pmid = 12672658 | doi = 10.1095/biolreprod.103.015867 | doi-access = free }} and, in yeasts, actin-like proteins are thought to play a role in the regulation of [[Epigenetics|gene expression]].{{cite journal | vauthors = Jiang YW, Stillman DJ | title = Epigenetic effects on yeast transcription caused by mutations in an actin-related protein present in the nucleus | journal = Genes & Development | volume = 10 | issue = 5 | pages = 604–619 | date = Mar 1996 | pmid = 8598290 | doi = 10.1101/gad.10.5.604 | doi-access = free }} In fact, actin is capable of acting as a transcription initiator when it reacts with a type of nuclear myosin that interacts with [[RNA polymerase]]s and other enzymes involved in the transcription process.{{cite journal | vauthors = Grummt I | title = Actin and myosin as transcription factors | journal = Current Opinion in Genetics & Development | volume = 16 | issue = 2 | pages = 191–196 | date = Apr 2006 | pmid = 16495046 | doi = 10.1016/j.gde.2006.02.001 }} [125] => * [[Stereocilia]] dynamics. Some cells develop fine filiform outgrowths on their surface that have a [[Somatosensory system|mechanosensory]] function. For example, this type of organelle is present in the [[Organ of Corti]], which is located in the [[ear]]. The main characteristic of these structures is that their length can be modified.{{cite journal | vauthors = Manor U, Kachar B | title = Dynamic length regulation of sensory stereocilia | journal = Seminars in Cell & Developmental Biology | volume = 19 | issue = 6 | pages = 502–510 | date = Dec 2008 | pmid = 18692583 | pmc = 2650238 | doi = 10.1016/j.semcdb.2008.07.006 }} The molecular architecture of the stereocilia includes a [[paracrystalline]] actin core in dynamic equilibrium with the monomers present in the adjacent cytosol. Type VI and VIIa myosins are present throughout this core, while myosin XVa is present in its extremities in quantities that are proportional to the length of the stereocilia.{{cite journal | vauthors = Rzadzinska AK, Schneider ME, Davies C, Riordan GP, Kachar B | title = An actin molecular treadmill and myosins maintain stereocilia functional architecture and self-renewal | journal = The Journal of Cell Biology | volume = 164 | issue = 6 | pages = 887–897 | date = Mar 2004 | pmid = 15024034 | pmc = 2172292 | doi = 10.1083/jcb.200310055 }} [126] => * Intrinsic [[chirality]]. Actomyosin networks have been implicated in generating an intrinsic chirality in individual cells.{{cite journal | vauthors = Xu J, Van Keymeulen A, Wakida NM, Carlton P, Berns MW, Bourne HR | title = Polarity reveals intrinsic cell chirality | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 104 | issue = 22 | pages = 9296–9300 | date = May 2007 | pmid = 17517645 | pmc = 1890488 | doi = 10.1073/pnas.0703153104 | bibcode = 2007PNAS..104.9296X | doi-access = free }} Cells grown out on chiral surfaces can show a directional left/right bias that is actomyosin dependent.{{cite journal | vauthors = Tamada A, Kawase S, Murakami F, Kamiguchi H | title = Autonomous right-screw rotation of growth cone filopodia drives neurite turning | journal = The Journal of Cell Biology | volume = 188 | issue = 3 | pages = 429–441 | date = Feb 2010 | pmid = 20123994 | pmc = 2819689 | doi = 10.1083/jcb.200906043 }}{{cite journal | vauthors = Wan LQ, Ronaldson K, Park M, Taylor G, Zhang Y, Gimble JM, Vunjak-Novakovic G | title = Micropatterned mammalian cells exhibit phenotype-specific left-right asymmetry | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 108 | issue = 30 | pages = 12295–12300 | date = Jul 2011 | pmid = 21709270 | pmc = 3145729 | doi = 10.1073/pnas.1103834108 | bibcode = 2011PNAS..10812295W | doi-access = free }} [127] => [128] => == Structure == [129] => [[File:1ATN image annotated.png|thumb|[[Ribbon diagram]] of an actin monomer from rabbit skeletal muscle, with the molecule's surface shown semi-transparent. The four subdomains as well as the bound ATP and calcium ion are annotated.]] [130] => [131] => Monomeric actin, or G-actin, has a globular structure consisting of two lobes separated by a deep cleft.{{sfn|Lodish|Berk|Kaiser|Krieger|2016|p=779}} The bottom of the cleft represents the "ATPase fold", a structure conserved among ATP and GTP-binding proteins that binds to a magnesium ion and a molecule of ATP.{{sfn|Lodish|Berk|Kaiser|Krieger|2016|p=779}} Binding of ATP or ADP is required to stabilize each actin monomer; without one of these molecules bound, actin quickly becomes [[Denaturation (biochemistry)|denatured]].{{sfn|Lodish|Berk|Kaiser|Krieger|2016|p=779}} [132] => [133] => The [[X-ray crystallography]] model of actin that was produced by Kabsch from the [[striated muscle tissue]] of [[European rabbit|rabbits]] is the most commonly used in structural studies as it was the first to be [[Separation process|purified]]. The G-actin crystallized by Kabsch is approximately 67 x 40 x 37 [[Angstrom|Å]] in size, has a [[molecular mass]] of 41,785 [[Dalton (unit)|Da]] and an estimated [[isoelectric point]] of 4.8. Its [[Electric charge|net charge]] at [[pH]] = 7 is -7. [134] => [135] => ;Primary structure [136] => [137] => Elzinga and co-workers first determined the complete [[peptide sequence]] for this type of actin in 1973, with later work by the same author adding further detail to the model. It contains 374 [[amino acid]] residues. Its [[N-terminus]] is highly [[acid]]ic and starts with an [[acetyl]]ed [[Aspartic acid|aspartate]] in its amino group. While its [[C-terminus]] is [[Base (chemistry)|alkaline]] and is formed by a [[phenylalanine]] preceded by a [[cysteine]], which has a degree of functional importance. Both extremes are in close proximity within the I-subdomain. An anomalous [[histidine|''N''τ-methylhistidine]] is located at position 73.{{cite journal | vauthors = Collins JH, Elzinga M | title = The primary structure of actin from rabbit skeletal muscle. Completion and analysis of the amino acid sequence | journal = The Journal of Biological Chemistry | volume = 250 | issue = 15 | pages = 5915–5920 | date = Aug 1975 | doi = 10.1016/S0021-9258(19)41139-3 | pmid = 1150665 | doi-access = free }} [138] => [139] => ;Tertiary structure — domains [140] => [141] => The tertiary structure is formed by two [[Protein domain|domains]] known as the large and the small, which are separated by a cleft centred around the location of the bond with [[adenosine triphosphate|ATP]]-[[adenosine diphosphate|ADP]]+[[phosphate|Pi]]. Below this there is a deeper notch called a "groove". In the [[Protein#Structure|native state]], despite their names, both have a comparable depth. [142] => [143] => The normal convention in [[topology|topological]] studies means that a protein is shown with the biggest domain on the left-hand side and the smallest domain on the right-hand side. In this position the smaller domain is in turn divided into two: subdomain I (lower position, residues 1–32, 70–144, and 338–374) and subdomain II (upper position, residues 33–69). The larger domain is also divided in two: subdomain III (lower, residues 145–180 and 270–337) and subdomain IV (higher, residues 181–269). The exposed areas of subdomains I and III are referred to as the "barbed" ends, while the exposed areas of domains II and IV are termed the "pointed" ends. This nomenclature refers to the fact that, due to the small mass of subdomain II actin is polar; the importance of this will be discussed below in the discussion on assembly dynamics. Some authors call the subdomains Ia, Ib, IIa, and IIb, respectively. [144] => [145] => ;Other important structures [146] => [147] => The most notable supersecondary structure is a five chain [[beta sheet]] that is composed of a β-meander and a β-α-β clockwise unit. It is present in both domains suggesting that the protein arose from gene duplication. [148] => * The [[Adenosine triphosphate|adenosine nucleotide]] binding site is located between two [[beta hairpin]]-shaped structures pertaining to the I and III domains. The residues that are involved are Asp11-Lys18 and Asp154-His161 respectively. [149] => * The [[cation|divalent cation]] binding site is located just below that for the adenosine nucleotide. ''In vivo'' it is most often formed by [[Magnesium|Mg2+]] or [[Calcium|Ca2+]] while ''in vitro'' it is formed by a chelating structure made up of [[lysine|Lys18]] and two [[oxygen]]s from the nucleotide's α-and β-[[phosphate]]s. This calcium is coordinated with six water molecules that are retained by the amino acids [[aspartic acid|Asp11]], Asp154, and [[glutamine|Gln137]]. They form a complex with the nucleotide that restricts the movements of the so-called "hinge" region, located between residues 137 and 144. This maintains the native form of the protein until its withdrawal [[Denaturation (biochemistry)|denatures]] the actin monomer. This region is also important because it determines whether the protein's cleft is in the "open" or "closed" conformation. [150] => * It is highly likely that there are at least three other centres with a lesser [[electron affinity|affinity]] (intermediate) and still others with a low affinity for divalent cations. It has been suggested that these centres may play a role in the polymerization of actin by acting during the activation stage. [151] => * There is a structure in subdomain 2 that is called the "D-loop" because it binds with [[DNase I]], it is located between the [[histidine|His40]] and [[glycine|Gly48]] residues. It has the appearance of a disorderly element in the majority of crystals, but it looks like a β-sheet when it is complexed with DNase I. It has been proposed that the key event in polymerization is probably the propagation of a conformational change from the centre of the bond with the nucleotide to this domain, which changes from a loop to a spiral. However, this hypothesis has been refuted by other studies.{{cite journal | vauthors = Rould MA, Wan Q, Joel PB, Lowey S, Trybus KM | title = Crystal structures of expressed non-polymerizable monomeric actin in the ADP and ATP states | journal = The Journal of Biological Chemistry | volume = 281 | issue = 42 | pages = 31909–31919 | date = Oct 2006 | pmid = 16920713 | doi = 10.1074/jbc.M601973200 | doi-access = free }} [152] => [153] => === F-actin === [154] => [[File:Actin filament atomic model.png|thumb|270px|F-actin; surface representation of a repetition of 13 subunits based on Ken Holmes' actin filament model{{cite journal | vauthors = Holmes KC, Popp D, Gebhard W, Kabsch W | title = Atomic model of the actin filament | journal = Nature | volume = 347 | issue = 6288 | pages = 44–49 | date = Sep 1990 | pmid = 2395461 | doi = 10.1038/347044a0 | bibcode = 1990Natur.347...44H | s2cid = 4317981 }}]] [155] => [156] => Under various conditions, G-actin molecules polymerize into longer threads called "filamentous-" or "F-actin". These F-actin threads are typically composed of two helical strands of actin wound around each other, forming a 7 to 9 [[nanometer]] wide helix that repeats every 72 nanometers (or every 14 G-actin subunits).{{sfn|Lodish|Berk|Kaiser|Krieger|2016|p=780}} In F-actin threads, G-actin molecules are all oriented in the same direction. The two ends of the F-actin thread are distinct from one another. At one end – designated the (−) end – the ATP-binding cleft of the terminal actin molecule is facing outward. At the opposite end – designated (+) – the ATP-binding cleft is buried in the filament, contacting the neighboring actin molecule.{{sfn|Lodish|Berk|Kaiser|Krieger|2016|p=780}} As F-actin threads grow, new molecules tend to join at the (+) end of an existing F-actin strand. Conversely, threads tend to shrink by shedding actin monomers from the strand's (-) end.{{sfn|Lodish|Berk|Kaiser|Krieger|2016|p=780}} [157] => [158] => Some proteins, such as [[cofilin]] appear to increase the angle of turn, but again this could be interpreted as the establishment of different structural states. These could be important in the polymerization process.{{cite journal | vauthors = Reisler E, Egelman EH | title = Actin structure and function: what we still do not understand | journal = The Journal of Biological Chemistry | volume = 282 | issue = 50 | pages = 36133–36137 | date = Dec 2007 | pmid = 17965017 | doi = 10.1074/jbc.R700030200 | doi-access = free }} [159] => [160] => There is less agreement regarding measurements of the turn radius and filament thickness: while the first models assigned a length of 25 Å, current X-ray diffraction data, backed up by cryo-electron microscopy suggests a length of 23.7 Å. These studies have shown the precise contact points between monomers. Some are formed with units of the same chain, between the "barbed" end on one monomer and the "pointed" end of the next one. While the monomers in adjacent chains make lateral contact through projections from subdomain IV, with the most important projections being those formed by the C-terminus and the hydrophobic link formed by three bodies involving residues 39–42, 201–203, and 286. This model suggests that a filament is formed by monomers in a "sheet" formation, in which the subdomains turn about themselves, this form is also found in the bacterial actin homologue [[MreB]]. [161] => [162] => The terms "pointed" and "barbed" referring to the two ends of the microfilaments derive from their appearance under [[transmission electron microscopy]] when samples are examined following a preparation technique called "decoration". This method consists of the addition of [[myosin]] S1 fragments to tissue that has been fixed with [[tannic acid]]. This myosin forms polar bonds with actin monomers, giving rise to a configuration that looks like arrows with feather fletchings along its shaft, where the shaft is the actin and the fletchings are the myosin. Following this logic, the end of the microfilament that does not have any protruding myosin is called the point of the arrow (- end) and the other end is called the barbed end (+ end).{{cite journal | vauthors = Begg DA, Rodewald R, Rebhun LI | title = The visualization of actin filament polarity in thin sections. Evidence for the uniform polarity of membrane-associated filaments | journal = The Journal of Cell Biology | volume = 79 | issue = 3 | pages = 846–852 | date = Dec 1978 | pmid = 569662 | pmc = 2110270 | doi = 10.1083/jcb.79.3.846 }} [163] => A S1 fragment is composed of the head and neck domains of [[myosin II]]. Under physiological conditions, G-actin (the [[monomer]] form) is transformed to F-actin (the [[polymer]] form) by ATP, where the role of ATP is essential.{{cite book | vauthors = Geneser F | title = Histologi | publisher = Munksgaard | year = 1981 | page = 105 | isbn = 978-87-16-08418-7 | url = https://books.google.com/books?id=-C3MOAAACAAJ }} [164] => [165] => The helical F-actin filament found in muscles also contains a [[tropomyosin]] molecule, which is a 40 [[nanometre]] long protein that is wrapped around the F-actin helix. During the resting phase the tropomyosin covers the actin's active sites so that the actin-myosin interaction cannot take place and produce muscular contraction. There are other protein molecules bound to the tropomyosin thread, these are the [[troponin]]s that have three polymers: [[troponin I]], [[troponin T]], and [[troponin C]].{{cite book | vauthors = Hall JE, Guyton AC | title = Textbook of medical physiology | url = https://archive.org/details/textbookmedicalp09guyt | url-access = limited | publisher = Elsevier Saunders | location = St. Louis, Mo | year = 2006 | page = [https://archive.org/details/textbookmedicalp09guyt/page/n111 76] | isbn = 978-0-7216-0240-0 }} [166] => [167] => F-actin is both [[Strength of materials|strong]] and dynamic. Unlike other [[polymer]]s, such as [[DNA]], whose constituent elements are bound together with [[covalent bond]]s, the monomers of actin filaments are assembled by weaker bonds.{{cite book |chapter=The Self-Assembly and Dynamic Structure of Cytoskeletal Filaments |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK26862/ |year=2002 | veditors = Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P |title=Molecular Biology of the Cell |publisher=Garland Science |isbn=978-0-8153-3218-3 |edition=4th }} The lateral bonds with neighbouring monomers resolve this anomaly, which in theory should weaken the structure as they can be broken by thermal agitation. In addition, the weak bonds give the advantage that the filament ends can easily release or incorporate monomers. This means that the filaments can be rapidly remodelled and can change cellular structure in response to an environmental stimulus. Which, along with the [[biochemical]] mechanism by which it is brought about is known as the "assembly dynamic". [168] => [169] => === Folding === [170] => [[File:Prefoldin.png|thumb|[[Molecular model|Ribbon model]] obtained using the [[PyMOL]] programme on [[X-ray crystallography|crystallographs]] ({{PDB|2ZDI}}) of the [[prefoldin]] proteins found in the [[archaea]]n ''[[Pyrococcus]] horikoshii''. The six supersecondary structures are present in a coiled helix "hanging" from the central [[beta barrel]]s. These are often compared in the literature to the [[tentacle]]s of a [[jellyfish]]. As far as is visible using [[Electron microscope|electron microscopy]], [[Eukaryote|eukariotic]] prefoldin has a similar structure.]] [171] => [172] => Actin can spontaneously acquire a large part of its [[Protein tertiary structure|tertiary structure]].{{cite journal | vauthors = Martín-Benito J, Boskovic J, Gómez-Puertas P, Carrascosa JL, Simons CT, Lewis SA, Bartolini F, Cowan NJ, Valpuesta JM | title = Structure of eukaryotic prefoldin and of its complexes with unfolded actin and the cytosolic chaperonin CCT | journal = The EMBO Journal | volume = 21 | issue = 23 | pages = 6377–6386 | date = Dec 2002 | pmid = 12456645 | pmc = 136944 | doi = 10.1093/emboj/cdf640 }} However, the way it acquires its [[Protein folding|fully functional form]] from its newly [[Translation (biology)|synthesized]] native form is special and almost unique in protein chemistry. The reason for this special route could be the need to avoid the presence of incorrectly folded actin monomers, which could be toxic as they can act as inefficient polymerization terminators. Nevertheless, it is key to establishing the stability of the cytoskeleton, and additionally, it is an essential process for coordinating the [[cell cycle]].{{cite journal | vauthors = Vandamme D, Lambert E, Waterschoot D, Cognard C, Vandekerckhove J, Ampe C, Constantin B, Rommelaere H | title = alpha-Skeletal muscle actin nemaline myopathy mutants cause cell death in cultured muscle cells | journal = Biochimica et Biophysica Acta (BBA) - Molecular Cell Research | volume = 1793 | issue = 7 | pages = 1259–1271 | date = Jul 2009 | pmid = 19393268 | doi = 10.1016/j.bbamcr.2009.04.004 | url = https://hal.science/hal-02880249/file/VandammeBBAMCR.pdf }}{{cite journal | vauthors = Brackley KI, Grantham J | title = Activities of the chaperonin containing TCP-1 (CCT): implications for cell cycle progression and cytoskeletal organisation | journal = Cell Stress & Chaperones | volume = 14 | issue = 1 | pages = 23–31 | date = Jan 2009 | pmid = 18595008 | pmc = 2673901 | doi = 10.1007/s12192-008-0057-x }} [173] => [174] => CCT is required in order to ensure that folding takes place correctly. CCT is a group II chaperonin, a large protein complex that assists in the folding of other proteins. CCT is formed of a double ring of eight different subunits (hetero-octameric) and it differs from group I chaperonins like [[GroEL]], which is found in Eubacteria and in eukaryotic organelles, as it does not require a co-chaperone to act as a lid over the central [[Catalysis|catalytic]] cavity. Substrates bind to CCT through specific domains. It was initially thought that it only bound with actin and [[tubulin]], although recent [[immunoprecipitation]] studies have shown that it interacts with a large number of [[polypeptide]]s, which possibly function as [[Enzyme substrate (biology)|substrates]]. It acts through ATP-dependent conformational changes that on occasion require several rounds of liberation and catalysis in order to complete a reaction.{{cite journal | vauthors = Stirling PC, Cuéllar J, Alfaro GA, El Khadali F, Beh CT, Valpuesta JM, Melki R, Leroux MR | title = PhLP3 modulates CCT-mediated actin and tubulin folding via ternary complexes with substrates | journal = The Journal of Biological Chemistry | volume = 281 | issue = 11 | pages = 7012–7021 | date = Mar 2006 | pmid = 16415341 | doi = 10.1074/jbc.M513235200 | doi-access = free }} [175] => [176] => In order to successfully complete their folding, both actin and tubulin need to interact with another protein called [[prefoldin]], which is a heterohexameric complex (formed by six distinct subunits), in an interaction that is so specific that the molecules have [[Coevolution|coevolved]]{{citation needed|date=July 2015}}. Actin complexes with prefoldin while it is still being formed, when it is approximately 145 [[amino acid]]s long, specifically those at the N-terminal.{{cite journal | vauthors = Hansen WJ, Cowan NJ, Welch WJ | title = Prefoldin-nascent chain complexes in the folding of cytoskeletal proteins | journal = The Journal of Cell Biology | volume = 145 | issue = 2 | pages = 265–277 | date = Apr 1999 | pmid = 10209023 | pmc = 2133115 | doi = 10.1083/jcb.145.2.265 }} [177] => [178] => Different recognition sub-units are used for actin or tubulin although there is some overlap. In actin the subunits that bind with prefoldin are probably PFD3 and PFD4, which bind in two places one between residues 60–79 and the other between residues 170–198. The actin is recognized, loaded, and delivered to the cytosolic chaperonin (CCT) in an open conformation by the inner end of prefoldin's "tentacles" (see the image and note). The contact when actin is delivered is so brief that a tertiary complex is not formed, immediately freeing the prefoldin.{{cite journal | vauthors = Simons CT, Staes A, Rommelaere H, Ampe C, Lewis SA, Cowan NJ | title = Selective contribution of eukaryotic prefoldin subunits to actin and tubulin binding | journal = The Journal of Biological Chemistry | volume = 279 | issue = 6 | pages = 4196–4203 | date = Feb 2004 | pmid = 14634002 | doi = 10.1074/jbc.M306053200 | doi-access = free }} [179] => [180] => [[File:CCT gamma apical.png|thumb|left|Ribbon model of the apical γ-domain of the [[Chaperone (protein)|chaperonin]] CCT]] [181] => [182] => The CCT then causes actin's sequential folding by forming bonds with its subunits rather than simply enclosing it in its cavity.{{cite journal | vauthors = Martín-Benito J, Grantham J, Boskovic J, Brackley KI, Carrascosa JL, Willison KR, Valpuesta JM | title = The inter-ring arrangement of the cytosolic chaperonin CCT | journal = EMBO Reports | volume = 8 | issue = 3 | pages = 252–257 | date = Mar 2007 | pmid = 17304242 | pmc = 1808031 | doi = 10.1038/sj.embor.7400894 }} This is why it possesses specific recognition areas in its apical β-domain. The first stage in the folding consists of the recognition of residues 245–249. Next, other determinants establish contact.{{cite journal | vauthors = Neirynck K, Waterschoot D, Vandekerckhove J, Ampe C, Rommelaere H | title = Actin interacts with CCT via discrete binding sites: a binding transition-release model for CCT-mediated actin folding | journal = Journal of Molecular Biology | volume = 355 | issue = 1 | pages = 124–138 | date = Jan 2006 | pmid = 16300788 | doi = 10.1016/j.jmb.2005.10.051 }} Both actin and tubulin bind to CCT in open conformations in the absence of ATP. In actin's case, two subunits are bound during each conformational change, whereas for tubulin binding takes place with four subunits. Actin has specific binding sequences, which interact with the δ and β-CCT subunits or with δ-CCT and ε-CCT. After AMP-PNP is bound to CCT the substrates move within the chaperonin's cavity. It also seems that in the case of actin, the [[CAP (protein)|CAP protein]] is required as a possible cofactor in actin's final folding states. [183] => [184] => The exact manner by which this process is regulated is still not fully understood, but it is known that the protein PhLP3 (a protein similar to [[phosducin]]) inhibits its activity through the formation of a tertiary complex. [185] => [186] => === ATPase's catalytic mechanism === [187] => Actin is an [[ATPase]], which means that it is an [[enzyme]] that [[hydrolysis|hydrolyzes]] ATP. This group of enzymes is characterised by their slow reaction rates. It is known that this ATPase is "active", that is, its speed increases by some 40,000 times when the actin forms part of a filament. A reference value for this rate of hydrolysis under ideal conditions is around 0.3 [[second|s−1]]. Then, the Pi remains bound to the actin next to the ADP for a long time, until it is cooperatively liberated from the interior of the filament.{{cite journal | vauthors = Vavylonis D, Yang Q, O'Shaughnessy B | title = Actin polymerization kinetics, cap structure, and fluctuations | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 102 | issue = 24 | pages = 8543–8548 | date = Jun 2005 | pmid = 15939882 | pmc = 1150824 | doi = 10.1073/pnas.0501435102 | bibcode = 2005PNAS..102.8543V | arxiv = q-bio/0404004 | doi-access = free }}{{cite journal | vauthors = Katkar HH, Davtyan A, Durumeric AE, Hocky GM, Schramm A, Enrique M, Voth GA |title=Insights into the cooperative nature of ATP hydrolysis in actin filaments |journal=Biophysical Journal |volume=115 |issue=8 |pages=1589–1602 |date=September 2018 |doi=10.1016/j.bpj.2018.08.034|pmid=30249402 |pmc=6260209 |bibcode=2018BpJ...115.1589K }} [188] => [189] => The exact molecular details of the catalytic mechanism are still not fully understood. Although there is much debate on this issue, it seems certain that a "closed" conformation is required for the hydrolysis of ATP, and it is thought that the residues that are involved in the process move to the appropriate distance. The [[glutamic acid]] Glu137 is one of the key residues, which is located in subdomain 1. Its function is to bind the water molecule that produces a [[nucleophile|nucleophilic attack]] on the ATP's γ-phosphate [[chemical bond|bond]], while the nucleotide is strongly bound to subdomains 3 and 4. The slowness of the catalytic process is due to the large distance and skewed position of the water molecule in relation to the reactant. It is highly likely that the conformational change produced by the rotation of the domains between actin's G and F forms moves the Glu137 closer allowing its hydrolysis. This model suggests that the polymerization and ATPase's function would be decoupled straight away. The "open" to "closed" transformation between G and F forms and its implications on the relative motion of several key residues and the formation of water wires have been characterized in [[molecular dynamics]] and [[QM/MM]] simulations.{{cite journal | vauthors = McCullagh M, Saunders MG, Voth GA | title = Unraveling the mystery of ATP hydrolysis in actin filaments | journal = Journal of the American Chemical Society | volume = 136 | issue = 37 | pages = 13053–13058 | date = September 2014 | pmid = 25181471 | pmc = 4183606 | doi = 10.1021/ja507169f }}{{cite journal | vauthors = Saunders MG, Voth GA | title = Water molecules in the nucleotide binding cleft of actin: effects on subunit conformation and implications for ATP hydrolysis | journal = Journal of Molecular Biology | volume = 413 | issue = 1 | pages = 279–291 | date = October 2011 | pmid = 21856312 | doi = 10.1016/j.jmb.2011.07.068 }} [190] => [191] => == Assembly dynamics == [192] => [[File:Thin filament formation.svg|thumb|Microfilament formation showing the polymerization mechanism for converting G-actin to F-actin; note the hydrolysis of the ATP.]] [193] => [194] => Actin filaments are often rapidly assembled and disassembled, allowing them to generate force and support cell movement.{{sfn|Lodish|Berk|Kaiser|Krieger|2016|p=781}} Assembly classically occurs in three steps. First, the "nucleation phase", in which two to three G-actin molecules slowly join to form a small oligomer that will nucleate further growth. Second, the "elongation phase", when the actin filament rapidly grows by the addition of many actin molecules to both ends. As the filament grows, actin molecules are added to the (+) end of the filament around 10 times faster than to the (−) end, and so filaments tend to primarily grow at the (+) end.{{sfn|Lodish|Berk|Kaiser|Krieger|2016|p=783}} Third, the "steady-state phase", where an equillibrium is reached as actin molecules join and leave the filament at the same rate, maintaining the filament's length.{{sfn|Lodish|Berk|Kaiser|Krieger|2016|p=781}} While the filament's length remains constant in the steady-state phase, new molecules are constantly being added to the (+) end and falling off the (−) end, a phenomenon called "treadmilling" as a given actin molecule would appear to move along the strand.{{sfn|Lodish|Berk|Kaiser|Krieger|2016|p=784}} In isolation, whether a filament will grow or shrink, and how quickly, are determined by the concentration of G-actin around the filament;{{sfn|Lodish|Berk|Kaiser|Krieger|2016|p=783}} however, in cells, the dynamics of actin filaments are heavily influenced by various [[actin-binding protein]]s. [195] => [199] => [200] => === Actin binding proteins === [201] => [202] => The actin cytoskeleton ''[[in vivo]]'' is not exclusively composed of actin, other proteins are required for its formation, continuance, and function. These proteins are called [[actin-binding protein]]s and they are involved in actin's polymerization, depolymerization, stability, and organisation.{{cite book | title = Biología celular | language = es | publisher = Elsevier España | year = 2002 | page = 132 | isbn = 978-84-458-1105-4 | url = https://books.google.com/books?id=54vSCCv33pYC }} The diversity of these proteins is such that actin is thought to be the protein that takes part in the greatest number of [[protein-protein interaction]]s.{{cite journal | vauthors = Dominguez R | title = Actin-binding proteins--a unifying hypothesis | journal = Trends in Biochemical Sciences | volume = 29 | issue = 11 | pages = 572–578 | date = Nov 2004 | pmid = 15501675 | doi = 10.1016/j.tibs.2004.09.004 }} [203] => [204] => [[File:Arp2 3 complex.png|thumb|Atomic structure of Arp2/3.{{cite journal | vauthors = Robinson RC, Turbedsky K, Kaiser DA, Marchand JB, Higgs HN, Choe S, Pollard TD | s2cid = 18088124 | title = Crystal structure of Arp2/3 complex | journal = Science | volume = 294 | issue = 5547 | pages = 1679–1684 | date = Nov 2001 | pmid = 11721045 | doi = 10.1126/science.1066333 | bibcode = 2001Sci...294.1679R }} Each colour corresponds to a subunit: Arp3, orange; Arp2, sea blue (subunits 1 and 2 are not shown); p40, green; p34, light blue; p20, dark blue; p21, magenta; p16, yellow.]] [205] => [206] => The nucleation of new actin filaments – the [[rate-limiting step]] in actin polymerization – is aided by actin-nucleating proteins such as [[formins]] (like [[formin-2]]) and the [[Arp2/3 complex]].{{sfn|Lodish|Berk|Kaiser|Krieger|2016|p=786}} Formins help to nucleate long actin filaments. They bind two free actin-ATP molecules, bringing them together. Then as the filament begins to grow, formin moves along the (+) end of the growing filament, all the while recruiting actin-binding proteins that promote filament growth, and excluding capping proteins that would block filament extension.{{sfn|Lodish|Berk|Kaiser|Krieger|2016|p=786}} Branches in actin filaments are typically nucleated by the [[Arp2/3 complex]] in concert with [[nucleation promoting factor]]s. Nucleation promoting factors bind two free G-actin molecules, then recruit and activate the Arp2/3 complex. The activated Arp2/3 complex attaches to an existing actin filament, and uses the two bound G-actin molecules to nucleate a new actin filament branching off of the old one at a 70° angle.{{sfn|Lodish|Berk|Kaiser|Krieger|2016|p=787–788}} [207] => [208] => [[File:Profilin actin complex.png|thumb|An actin (green) - profilin (blue) complex.{{PDB|2BTF}}; {{cite journal | vauthors = Schutt CE, Myslik JC, Rozycki MD, Goonesekere NC, Lindberg U | title = The structure of crystalline profilin-beta-actin | journal = Nature | volume = 365 | issue = 6449 | pages = 810–816 | date = Oct 1993 | pmid = 8413665 | doi = 10.1038/365810a0 | bibcode = 1993Natur.365..810S | s2cid = 4359724 }} The profilin shown belongs to group II, normally present in the [[kidney]]s and the [[brain]].]] [209] => [210] => As filaments grow, the pool of available G-actin molecules is managed by G-actin-binding proteins such as [[profilin]] and [[Thymosins|thymosin β-4]]. [[Profilin]] ensures a supply of available actin-ATP by binding to ADP-bound G-actin and promoting the exchange of ADP for ATP. Profilin's binding to the actin molecule physically blocks its addition to a filament's (−) end, but permits it to join the (+) end. Once the actin-ATP has joined the filament, profilin releases it.{{sfn|Lodish|Berk|Kaiser|Krieger|2016|p=784}} As formins promote the nucleation and extension of new actin filaments, they recruit profilin to the area, increasing the local concentration of actin-ATP to boost filament growth.{{sfn|Lodish|Berk|Kaiser|Krieger|2016|p=786}} In contrast, thymosin β-4 binds and sequesters actin-ATP, preventing it from joining a microfilament.{{sfn|Lodish|Berk|Kaiser|Krieger|2016|p=785}} [211] => [212] => Once an actin fiber is established, the dynamics of its growth or collapse are influenced by numerous proteins. Existing strands can be interrupted by filament cleaving proteins, such as [[cofilin]] and [[gelsolin]]. Cofilin binds along two actin-ADP molecules in a filament, forcing a movement that destabilizes the filament and causes it to break.{{sfn|Lodish|Berk|Kaiser|Krieger|2016|pp=784–785}} Gelsolin inserts itself between actin molecules in a filament, disrupting the filament. After the filament breaks, gelsolin remains attached to the new (+) end, preventing it from growing, thus forcing its disassembly.{{sfn|Lodish|Berk|Kaiser|Krieger|2016|p=785}} [213] => [214] => [[File:Gelsolin.png|thumb|left|The protein [[gelsolin]], which is a key regulator in the assembly and disassembly of actin.]] [215] => [216] => Other proteins bind to the ends of actin filaments, stabilizing them. These are called "capping proteins" and include [[CapZ]] and [[tropomodulin]]. CapZ binds the (+) end of a filament, preventing further addition or loss of actin from that end.{{sfn|Lodish|Berk|Kaiser|Krieger|2016|p=785}} [[Tropomodulin]] binds to a filament's (−) end, again preventing addition or loss of molecule's at that end. Tropomodulin is typically found in cells that require extremely stable actin filaments, such as those in muscle and red blood cells.{{sfn|Lodish|Berk|Kaiser|Krieger|2016|p=785}} [217] => [218] => These actin binding proteins are typically regulated by various cellular signals to control actin assembly dynamics in different cellular locations. Formins, for example, are typically folded in an inactive conformation until they're activated by the binding of the [[small GTPase]] [[Rho family of GTPases|Rho]].{{sfn|Lodish|Berk|Kaiser|Krieger|2016|p=786}} Actin branching at the cell membrane is important for cell movement, and so the plasma membrane lipid [[Phosphatidylinositol 4,5-bisphosphate|PIP2]] activates the nucleation promoting factor [[Wiskott–Aldrich syndrome protein|WASp]] and inhibits CapZ.{{sfn|Lodish|Berk|Kaiser|Krieger|2016|pp=785, 788}} WASp is also activated by the small GTPase [[Cdc42]], while another nucleation promoting factor WAVE is activated by the GTPase [[Rac1]].{{sfn|Lodish|Berk|Kaiser|Krieger|2016|pp=788–789}} [219] => [220] => == Genetics == [221] => [[File:Adherens Junctions structural proteins.svg|thumb|350px|Principal interactions of structural proteins are at [[cadherin]]-based adherens junction. Actin filaments are linked to α-[[actinin]] and to the membrane through [[vinculin]]. The head domain of vinculin associates to E-cadherin via [[α-catenin]], [[β-catenin]], and [[γ-catenin]]. The tail domain of vinculin binds to membrane lipids and to actin filaments.]] [222] => [223] => Although most [[yeast]]s have only a single actin gene, higher [[eukaryote]]s, in general, [[gene expression|express]] several [[isoform]]s of actin encoded by a family of related genes. [[Mammal]]s have at least six actin isoforms coded by separate genes,{{cite journal | vauthors = Vandekerckhove J, Weber K | title = At least six different actins are expressed in a higher mammal: an analysis based on the amino acid sequence of the amino-terminal tryptic peptide | journal = Journal of Molecular Biology | volume = 126 | issue = 4 | pages = 783–802 | date = Dec 1978 | pmid = 745245 | doi = 10.1016/0022-2836(78)90020-7 }} which are divided into three classes – alpha, beta, and gamma – according to their [[isoelectric point]]s. In general, alpha actins are found in muscle ([[ACTA1|α-skeletal]], [[ACTA2|α-aortic smooth]], [[ACTC1|α-cardiac]]), whereas beta and gamma isoforms are prominent in non-muscle cells ([[Beta-actin|β-cytoplasmic]], [[ACTG1|γ1-cytoplasmic]], [[ACTG2|γ2-enteric smooth]]). Although the amino acid sequences and ''[[in vitro]]'' properties of the isoforms are highly similar, these isoforms cannot completely substitute for one another ''[[in vivo]]''.{{Cite book | vauthors = Khaitlina SY | title = Functional specificity of actin isoforms | volume = 202 | pages = 35–98 | year = 2001 | pmid = 11061563 | doi = 10.1016/S0074-7696(01)02003-4 | series = International Review of Cytology | isbn = 9780123646064 }} Plants contains more than 60 actin genes and [[pseudogene]]s.{{sfn|Lodish|Berk|Kaiser|Krieger|2016|p=779}} [224] => [225] => The typical actin gene has an approximately 100-nucleotide [[5' UTR]], a 1200-nucleotide [[Translation (genetics)|translated]] region, and a 200-nucleotide [[3' UTR]]. The majority of actin genes are interrupted by [[intron]]s, with up to six introns in any of 19 well-characterised locations. The high conservation of the family makes actin the favoured model for studies comparing the introns-early and introns-late models of intron evolution. [226] => [227] => == Evolution == [228] => Actin and closely related proteins are present in all organisms, suggesting the common ancestor of all life on Earth had actin.{{sfn|Pollard|2016|loc="Genes, sequence conservation, distribution, and abundance"}} Actin is one of the most [[Conservation (genetics)|conserved]] proteins throughout the evolution of eukaryotes. The sequences of actin proteins from animals and [[amoeba]]e are 80% identical despite being separated by approximately one billion years of evolution.{{sfn|Lodish|Berk|Kaiser|Krieger|2016|p=779}} Many [[unicellular]] eukaryotes have a single actin gene, while multicellular eukaryotes often have several closely related genes that serve specialized functions. Humans have six; plants have 10 or more.{{sfn|Pollard|2016|loc="Genes, sequence conservation, distribution, and abundance"}} In addition to actin, eukaryotes have a large family of actin-related proteins, or "Arps", that share a common ancestor with actin and are called Arp1–Arp11, with Arp1 the most closely related to actin, and Arp11 the least.{{sfn|Pollard|2016|loc="Genes, sequence conservation, distribution, and abundance"}} [229] => [230] => Bacteria encode three types of actin: [[MreB]] influences cell shape, [[FtsA]] cell division, and [[ParM]] separation of large [[plasmid]]s.{{sfn|Pollard|2016|loc="Genes, sequence conservation, distribution, and abundance"}} Some [[archaea]] have a bacteria-like MreB gene, while others have an actin gene that more closely resembles eukaryote actin.{{sfn|Pollard|2016|loc="Genes, sequence conservation, distribution, and abundance"}} [231] => [232] => The eukaryotic cytoskeleton of organisms among all [[Phylogenetic|taxonomic groups]] have similar components to actin and tubulin. For example, the protein that is coded by the ''[[ACTG2]]'' gene in humans is completely equivalent to the [[Homology (biology)|homologues]] present in rats and mice, even though at a [[nucleotide]] level the similarity decreases to 92%. However, there are major differences with the equivalents in prokaryotes ([[FtsZ]] and [[MreB]]), where the similarity between nucleotide sequences is between 40 and 50% among different [[bacteria]] and [[archaea]] species. Some authors suggest that the ancestral protein that gave rise to the model eukaryotic actin resembles the proteins present in modern bacterial cytoskeletons.{{cite journal | vauthors = Erickson HP | title = Evolution of the cytoskeleton | journal = BioEssays | volume = 29 | issue = 7 | pages = 668–677 | date = Jul 2007 | pmid = 17563102 | pmc = 2630885 | doi = 10.1002/bies.20601 }} [233] => [234] => [[File:MreB.png|thumb|Structure of [[MreB]], a bacterial protein whose three-dimensional structure resembles that of G-actin]] [235] => [236] => Some authors point out that the behaviour of actin, tubulin, and [[histone]], a protein involved in the stabilization and regulation of DNA, are similar in their ability to bind nucleotides and in their ability of take advantage of [[Brownian motion]]. It has also been suggested that they all have a common ancestor.{{cite journal | vauthors = Gardiner J, McGee P, Overall R, Marc J | title = Are histones, tubulin, and actin derived from a common ancestral protein? | journal = Protoplasma | volume = 233 | issue = 1–2 | pages = 1–5 | year = 2008 | pmid = 18615236 | doi = 10.1007/s00709-008-0305-z | s2cid = 21765920 }} Therefore, [[evolution]]ary processes resulted in the diversification of ancestral proteins into the varieties present today, conserving, among others, actins as efficient molecules that were able to tackle essential ancestral biological processes, such as [[endocytosis]].{{cite journal | vauthors = Galletta BJ, Cooper JA | title = Actin and endocytosis: mechanisms and phylogeny | journal = Current Opinion in Cell Biology | volume = 21 | issue = 1 | pages = 20–27 | date = Feb 2009 | pmid = 19186047 | pmc = 2670849 | doi = 10.1016/j.ceb.2009.01.006 }} [237] => [238] => The [[Arp2/3 complex]] is widely found in all [[Eukaryote|eukaryotic]] organisms.{{cite journal | vauthors = Mullins RD, Pollard TD | title = Structure and function of the Arp2/3 complex | journal = Current Opinion in Structural Biology | volume = 9 | issue = 2 | pages = 244–249 | date = Apr 1999 | pmid = 10322212 | doi = 10.1016/S0959-440X(99)80034-7 }} [239] => [240] => ===Equivalents in prokaryotes=== [241] => The [[Cytoskeleton#Prokaryotic cytoskeleton|bacterial cytoskeleton]] contains proteins that are highly similar to actin monomers and polymers. The bacterial protein [[MreB]] polymerizes into thin non-helical filaments and occasionally into helical structures similar to F-actin.{{cite journal | vauthors = Popp D, Narita A, Maeda K, Fujisawa T, Ghoshdastider U, Iwasa M, Maéda Y, Robinson RC | title = Filament structure, organization, and dynamics in MreB sheets | journal = The Journal of Biological Chemistry | volume = 285 | issue = 21 | pages = 15858–15865 | date = May 2010 | pmid = 20223832 | pmc = 2871453 | doi = 10.1074/jbc.M109.095901 | doi-access = free }} Furthermore, its crystalline structure is very similar to that of G-actin (in terms of its three-dimensional conformation), there are even similarities between the MreB protofilaments and F-actin. The bacterial cytoskeleton also contains the [[FtsZ]] proteins, which are similar to [[tubulin]].{{cite journal | vauthors = van den Ent F, Amos LA, Löwe J | title = Prokaryotic origin of the actin cytoskeleton | journal = Nature | volume = 413 | issue = 6851 | pages = 39–44 | date = Sep 2001 | pmid = 11544518 | doi = 10.1038/35092500 | bibcode = 2001Natur.413...39V | s2cid = 4427828 }} [242] => [243] => Bacteria therefore possess a cytoskeleton with homologous elements to actin (for example, MreB, AlfA, [[ParM]], [[FtsA]], and MamK), even though the amino acid sequence of these proteins diverges from that present in animal cells. However, such proteins have a high degree of [[protein structure|structural]] similarity to eukaryotic actin. The highly dynamic microfilaments formed by the aggregation of MreB and ParM are essential to cell viability and they are involved in cell morphogenesis, [[chromosome]] segregation, and cell polarity. ParM is an actin homologue that is coded in a [[plasmid]] and it is involved in the regulation of plasmid DNA.{{cite journal | vauthors = Carballido-López R | title = The bacterial actin-like cytoskeleton | journal = Microbiology and Molecular Biology Reviews | volume = 70 | issue = 4 | pages = 888–909 | date = Dec 2006 | pmid = 17158703 | pmc = 1698507 | doi = 10.1128/MMBR.00014-06 }} ParMs from different bacterial plasmids can form astonishingly diverse helical structures comprising two{{cite journal | vauthors = Popp D, Xu W, Narita A, Brzoska AJ, Skurray RA, Firth N, Ghoshdastider U, Goshdastider U, Maéda Y, Robinson RC, Schumacher MA | title = Structure and filament dynamics of the pSK41 actin-like ParM protein: implications for plasmid DNA segregation | journal = The Journal of Biological Chemistry | volume = 285 | issue = 13 | pages = 10130–10140 | date = Mar 2010 | pmid = 20106979 | pmc = 2843175 | doi = 10.1074/jbc.M109.071613 | doi-access = free }}{{cite journal | vauthors = Popp D, Narita A, Ghoshdastider U, Maeda K, Maéda Y, Oda T, Fujisawa T, Onishi H, Ito K, Robinson RC | title = Polymeric structures and dynamic properties of the bacterial actin AlfA | journal = Journal of Molecular Biology | volume = 397 | issue = 4 | pages = 1031–1041 | date = Apr 2010 | pmid = 20156449 | doi = 10.1016/j.jmb.2010.02.010 }} or four{{cite journal | vauthors = Popp D, Narita A, Lee LJ, Ghoshdastider U, Xue B, Srinivasan R, Balasubramanian MK, Tanaka T, Robinson RC | title = Novel actin-like filament structure from Clostridium tetani | journal = The Journal of Biological Chemistry | volume = 287 | issue = 25 | pages = 21121–21129 | date = Jun 2012 | pmid = 22514279 | pmc = 3375535 | doi = 10.1074/jbc.M112.341016 | doi-access = free }} strands to maintain faithful plasmid inheritance. [244] => [245] => In [[archaea]] the homologue Ta0583 is even more similar to the eukaryotic actins.{{cite journal | vauthors = Hara F, Yamashiro K, Nemoto N, Ohta Y, Yokobori S, Yasunaga T, Hisanaga S, Yamagishi A | title = An actin homolog of the archaeon Thermoplasma acidophilum that retains the ancient characteristics of eukaryotic actin | journal = Journal of Bacteriology | volume = 189 | issue = 5 | pages = 2039–2045 | date = Mar 2007 | pmid = 17189356 | pmc = 1855749 | doi = 10.1128/JB.01454-06 }} [246] => [247] => == Molecular pathology == [248] => The majority of [[mammal]]s possess six different actin [[gene]]s. Of these, two code for the [[cytoskeleton]] (''[[ACTB]]'' and ''[[ACTG1]]'') while the other four are involved in [[skeletal striated muscle]] (''[[ACTA1]]''), [[smooth muscle tissue]] (''[[ACTA2]]''), [[Intestine|intestinal]] muscles (''[[ACTG2]]'') and [[cardiac muscle]] (''[[ACTC1]]''). The actin in the cytoskeleton is involved in the [[Pathogenesis|pathogenic]] mechanisms of many [[Pathogen|infectious agents]], including [[HIV]]. The vast majority of the [[mutation]]s that affect actin are point mutations that have a [[Dominance (genetics)|dominant effect]], with the exception of six mutations involved in [[nemaline myopathy]]. This is because in many cases the mutant of the actin monomer acts as a "cap" by preventing the elongation of F-actin. [249] => [250] => === Pathology associated with ''ACTA1'' === [251] => ''[[ACTA1]]'' is the gene that codes for the α-[[isoform]] of actin that is predominant in human [[skeletal striated muscle]]s, although it is also expressed in heart muscle and in the [[Thyroid|thyroid gland]].{{cite journal | vauthors = Su AI, Wiltshire T, Batalov S, Lapp H, Ching KA, Block D, Zhang J, Soden R, Hayakawa M, Kreiman G, Cooke MP, Walker JR, Hogenesch JB | title = A gene atlas of the mouse and human protein-encoding transcriptomes | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 16 | pages = 6062–6067 | date = Apr 2004 | pmid = 15075390 | pmc = 395923 | doi = 10.1073/pnas.0400782101 | bibcode = 2004PNAS..101.6062S | doi-access = free }} Its [[DNA sequence]] consists of seven [[exon]]s that produce five known [[Transcription (genetics)|transcripts]].{{cite web | url = https://www.uniprot.org/uniprot/P68133 | title = ACTS_HUMAN | publisher = UniProt Consortium | website = P68133 | access-date = 2013-01-21 | url-status = live | archive-url = https://web.archive.org/web/20121105073449/http://www.uniprot.org/uniprot/P68133 | archive-date = 2012-11-05 }} The majority of these consist of point mutations causing substitution of [[amino acid]]s. The mutations are in many cases associated with a [[phenotype]] that determines the severity and the course of the affliction.{{cite book | vauthors = Dos Remedios CG, Chhabra D | title =Actin-binding Proteins and Disease | year =2008 | publisher = Springer | isbn = 978-0-387-71747-0 | url = https://books.google.com/books?id=Y6xHVnH8iOIC&q=actinopathy&pg=PA23 }} [252] => [253] => [[File:Nemaline rods.jpg|thumb|Giant [[Nemaline myopathy|nemaline rods]] produced by the [[transfection]] of a [[DNA sequence]] of ''[[ACTA1]]'', which is the carrier of a [[mutation]] responsible for nemaline myopathy]] [254] => [255] => The mutation alters the structure and function of skeletal muscles producing one of three forms of [[myopathy]]: type 3 [[nemaline myopathy]], [[Congenital myopathy|congenital myopathy with an excess of thin myofilaments]] (CM) and [[Congenital myopathy#Congenital fiber type disproportion|congenital myopathy with fibre type disproportion]] (CMFTD). Mutations have also been found that produce [[Central core disease|core myopathies]].{{cite journal | vauthors = Kaindl AM, Rüschendorf F, Krause S, Goebel HH, Koehler K, Becker C, Pongratz D, Müller-Höcker J, Nürnberg P, Stoltenburg-Didinger G, Lochmüller H, Huebner A | title = Missense mutations of ACTA1 cause dominant congenital myopathy with cores | journal = Journal of Medical Genetics | volume = 41 | issue = 11 | pages = 842–848 | date = Nov 2004 | pmid = 15520409 | pmc = 1735626 | doi = 10.1136/jmg.2004.020271 }} Although their phenotypes are similar, in addition to typical nemaline myopathy some specialists distinguish another type of myopathy called actinic nemaline myopathy. In the former, clumps of actin form instead of the typical rods. It is important to state that a patient can show more than one of these [[phenotype]]s in a [[biopsy]].{{cite journal | vauthors = Sparrow JC, Nowak KJ, Durling HJ, Beggs AH, Wallgren-Pettersson C, Romero N, Nonaka I, Laing NG | title = Muscle disease caused by mutations in the skeletal muscle alpha-actin gene (ACTA1) | journal = Neuromuscular Disorders | volume = 13 | issue = 7–8 | pages = 519–531 | date = Sep 2003 | pmid = 12921789 | doi = 10.1016/S0960-8966(03)00101-9 | s2cid = 20716 }} The most common [[symptom]]s consist of a typical facial morphology (myopathic [[Facies (medical)|facies]]), muscular weakness, a delay in motor development and respiratory difficulties. The course of the illness, its gravity, and the age at which it appears are all variable and overlapping forms of myopathy are also found. A symptom of nemaline myopathy is that "nemaline rods" appear in differing places in type 1 muscle fibres. These rods are non-[[pathognomonic]] structures that have a similar composition to the Z disks found in the [[sarcomere]].{{cite book | veditors = Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP | title = GeneReviews [Internet] | vauthors = North K, Ryan MM | chapter = Nemaline Myopathy | year = 2002 | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK1288/ | publisher = University of Washington, Seattle | location = Seattle (WA) | pmid = 20301465 | url-status = live | archive-url = https://web.archive.org/web/20170118124142/https://www.ncbi.nlm.nih.gov/books/NBK1288/ | archive-date = 2017-01-18 }} [256] => [257] => The [[pathogenesis]] of this myopathy is very varied. Many mutations occur in the region of actin's indentation near to its [[nucleotide]] binding sites, while others occur in Domain 2, or in the areas where interaction occurs with associated proteins. This goes some way to explain the great variety of clumps that form in these cases, such as Nemaline or Intranuclear Bodies or Zebra Bodies. Changes in actin's [[Protein folding|folding]] occur in nemaline myopathy as well as changes in its aggregation and there are also changes in the [[Gene expression|expression]] of other associated proteins. In some variants where intranuclear bodies are found the changes in the folding masks the [[Nuclear pore#Export of proteins|nucleus's protein exportation signal]] so that the accumulation of actin's mutated form occurs in the [[cell nucleus]].{{cite journal | vauthors = Ilkovski B, Nowak KJ, Domazetovska A, Maxwell AL, Clement S, Davies KE, Laing NG, North KN, Cooper ST | title = Evidence for a dominant-negative effect in ACTA1 nemaline myopathy caused by abnormal folding, aggregation and altered polymerization of mutant actin isoforms | journal = Human Molecular Genetics | volume = 13 | issue = 16 | pages = 1727–1743 | date = Aug 2004 | pmid = 15198992 | doi = 10.1093/hmg/ddh185 | doi-access = free }} On the other hand, it appears that mutations to ''ACTA1'' that give rise to a CFTDM have a greater effect on sarcomeric function than on its structure.{{cite journal | vauthors = Clarke NF, Ilkovski B, Cooper S, Valova VA, Robinson PJ, Nonaka I, Feng JJ, Marston S, North K | title = The pathogenesis of ACTA1-related congenital fiber type disproportion | journal = Annals of Neurology | volume = 61 | issue = 6 | pages = 552–561 | date = Jun 2007 | pmid = 17387733 | doi = 10.1002/ana.21112 | s2cid = 11746835 }} Recent investigations have tried to understand this apparent paradox, which suggests there is no clear correlation between the number of rods and muscular weakness. It appears that some mutations are able to induce a greater [[apoptosis]] rate in type II muscular fibres. [258] => [259] => [[File:Mutations in alpha actin.jpg|thumb|left|200px|Position of seven [[genetic mutation|mutations]] relevant to the various actinopathies related to ''[[ACTA1]]''{{cite journal | vauthors = Bathe FS, Rommelaere H, Machesky LM | title = Phenotypes of myopathy-related actin mutants in differentiated C2C12 myotubes | journal = BMC Cell Biology | volume = 8 | issue = 1 | pages = 2 | year = 2007 | pmid = 17227580 | pmc = 1779783 | doi = 10.1186/1471-2121-8-2 | doi-access = free }}]] [260] => [261] => === In smooth muscle === [262] => There are two isoforms that code for actins in the [[smooth muscle tissue]]: [263] => [264] => ''[[ACTG2]]'' codes for the largest actin isoform, which has nine [[exon]]s, one of which, the one located at the 5' end, is not [[Translation (biology)|translated]].{{cite journal | vauthors = Miwa T, Manabe Y, Kurokawa K, Kamada S, Kanda N, Bruns G, Ueyama H, Kakunaga T | title = Structure, chromosome location, and expression of the human smooth muscle (enteric type) gamma-actin gene: evolution of six human actin genes | journal = Molecular and Cellular Biology | volume = 11 | issue = 6 | pages = 3296–3306 | date = Jun 1991 | pmid = 1710027 | pmc = 360182 | doi = 10.1128/mcb.11.6.3296 }} It is a γ-actin that is expressed in the enteric smooth muscle. No mutations to this gene have been found that correspond to pathologies, although [[DNA microarray|microarrays]] have shown that this protein is more often expressed in cases that are resistant to [[chemotherapy]] using [[cisplatin]].{{cite journal | vauthors = Watson MB, Lind MJ, Smith L, Drew PJ, Cawkwell L | title = Expression microarray analysis reveals genes associated with in vitro resistance to cisplatin in a cell line model | journal = Acta Oncologica | volume = 46 | issue = 5 | pages = 651–658 | year = 2007 | pmid = 17562441 | doi = 10.1080/02841860601156157 | s2cid = 7163200 | doi-access = free }} [265] => [266] => ''[[ACTA2]]'' codes for an α-actin located in the smooth muscle, and also in vascular smooth muscle. It has been noted that the MYH11 mutation could be responsible for at least 14% of hereditary [[Aortic aneurism|thoracic aortic aneurisms]] particularly Type 6. This is because the mutated variant produces an incorrect filamentary assembly and a reduced capacity for vascular smooth muscle contraction. Degradation of the [[Aorta|aortic media]] has been recorded in these individuals, with areas of disorganization and [[hyperplasia]] as well as [[stenosis]] of the aorta's [[vasa vasorum]].{{cite journal | vauthors = Guo DC, Pannu H, Tran-Fadulu V, Papke CL, Yu RK, Avidan N, Bourgeois S, Estrera AL, Safi HJ, Sparks E, Amor D, Ades L, McConnell V, Willoughby CE, Abuelo D, Willing M, Lewis RA, Kim DH, Scherer S, Tung PP, Ahn C, Buja LM, Raman CS, Shete SS, Milewicz DM | title = Mutations in smooth muscle alpha-actin (ACTA2) lead to thoracic aortic aneurysms and dissections | journal = Nature Genetics | volume = 39 | issue = 12 | pages = 1488–1493 | date = Dec 2007 | pmid = 17994018 | doi = 10.1038/ng.2007.6 | s2cid = 62785801 }} The number of afflictions that the gene is implicated in is increasing. It has been related to [[Moyamoya disease]] and it seems likely that certain mutations in heterozygosis could confer a predisposition to many vascular pathologies, such as thoracic aortic aneurysm and [[ischaemic heart disease]].{{cite journal | vauthors = Guo DC, Papke CL, Tran-Fadulu V, Regalado ES, Avidan N, Johnson RJ, Kim DH, Pannu H, Willing MC, Sparks E, Pyeritz RE, Singh MN, Dalman RL, Grotta JC, Marian AJ, Boerwinkle EA, Frazier LQ, LeMaire SA, Coselli JS, Estrera AL, Safi HJ, Veeraraghavan S, Muzny DM, Wheeler DA, Willerson JT, Yu RK, Shete SS, Scherer SE, Raman CS, Buja LM, Milewicz DM | title = Mutations in smooth muscle alpha-actin (ACTA2) cause coronary artery disease, stroke, and Moyamoya disease, along with thoracic aortic disease | journal = American Journal of Human Genetics | volume = 84 | issue = 5 | pages = 617–627 | date = May 2009 | pmid = 19409525 | pmc = 2680995 | doi = 10.1016/j.ajhg.2009.04.007 }} The α-actin found in smooth muscles is also an interesting marker for evaluating the progress of liver [[cirrhosis]].{{cite journal | vauthors = Akpolat N, Yahsi S, Godekmerdan A, Yalniz M, Demirbag K | title = The value of alpha-SMA in the evaluation of hepatic fibrosis severity in hepatitis B infection and cirrhosis development: a histopathological and immunohistochemical study | journal = Histopathology | volume = 47 | issue = 3 | pages = 276–280 | date = Sep 2005 | pmid = 16115228 | doi = 10.1111/j.1365-2559.2005.02226.x | s2cid = 23800095 }} [267] => [268] => === In heart muscle === [269] => The ''[[ACTC1]]'' gene codes for the α-actin isoform present in heart muscle. It was first sequenced by Hamada and co-workers in 1982, when it was found that it is interrupted by five introns.{{cite journal | vauthors = Hamada H, Petrino MG, Kakunaga T | title = Molecular structure and evolutionary origin of human cardiac muscle actin gene | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 79 | issue = 19 | pages = 5901–5905 | date = Oct 1982 | pmid = 6310553 | pmc = 347018 | doi = 10.1073/pnas.79.19.5901 | bibcode = 1982PNAS...79.5901H | doi-access = free }} It was the first of the six genes where alleles were found that were implicated in pathological processes.{{cite journal | vauthors = Olson TM, Michels VV, Thibodeau SN, Tai YS, Keating MT | s2cid = 26971894 | title = Actin mutations in dilated cardiomyopathy, a heritable form of heart failure | journal = Science | volume = 280 | issue = 5364 | pages = 750–752 | date = May 1998 | pmid = 9563954 | doi = 10.1126/science.280.5364.750 | bibcode = 1998Sci...280..750O }} [270] => [271] => [[File:Myocardiopathy dilated2.JPG|thumb|Cross section of a [[Muridae|rat]] [[heart]] that is showing signs of [[dilated cardiomyopathy]]{{cite journal | vauthors = Xia XG, Zhou H, Samper E, Melov S, Xu Z | title = Pol II-expressed shRNA knocks down Sod2 gene expression and causes phenotypes of the gene knockout in mice | journal = PLOS Genetics | volume = 2 | issue = 1 | pages = e10 | date = Jan 2006 | pmid = 16450009 | pmc = 1358942 | doi = 10.1371/journal.pgen.0020010 | doi-access = free }}]] [272] => [273] => A number of structural disorders associated with point mutations of this gene have been described that cause malfunctioning of the heart, such as Type 1R [[dilated cardiomyopathy]] and Type 11 [[hypertrophic cardiomyopathy]]. Certain defects of the [[Atrium (heart)|atrial septum]] have been described recently that could also be related to these mutations.{{OMIM|102540|Actin, alpha, cardiac muscle; ACTC1}}{{cite journal | vauthors = Matsson H, Eason J, Bookwalter CS, Klar J, Gustavsson P, Sunnegårdh J, Enell H, Jonzon A, Vikkula M, Gutierrez I, Granados-Riveron J, Pope M, Bu'Lock F, Cox J, Robinson TE, Song F, Brook DJ, Marston S, Trybus KM, Dahl N | title = Alpha-cardiac actin mutations produce atrial septal defects | journal = Human Molecular Genetics | volume = 17 | issue = 2 | pages = 256–265 | date = Jan 2008 | pmid = 17947298 | doi = 10.1093/hmg/ddm302 | doi-access = free }} [274] => [275] => Two cases of dilated cardiomyopathy have been studied involving a substitution of highly conserved [[amino acid]]s belonging to the [[protein domains]] that bind and intersperse with the [[sarcomere|Z discs]]. This has led to the theory that the dilation is produced by a defect in the transmission of [[muscle contraction|contractile force]] in the [[myocyte]]s.{{cite book | vauthors = Devlin TM | title = Bioquimica | publisher = Reverté | location = Barcelona | year = 2006 | isbn = 978-84-291-7208-9 | url = https://books.google.com/books?id=p3DCb9lTLx8C&q=la+miosina+se+une+a+la+actina+residuo&pg=PA1021 }} [276] => [277] => The mutations in ACTC1 are responsible for at least 5% of hypertrophic cardiomyopathies.{{cite thesis | vauthors = Kabaeva Z |title=Genetic analysis in hypertrophic cardiomyopathy |date=11 November 2002 |doi=10.18452/14800 }} The existence of a number of point mutations have also been found:{{cite journal | vauthors = Olson TM, Doan TP, Kishimoto NY, Whitby FG, Ackerman MJ, Fananapazir L | title = Inherited and de novo mutations in the cardiac actin gene cause hypertrophic cardiomyopathy | journal = Journal of Molecular and Cellular Cardiology | volume = 32 | issue = 9 | pages = 1687–1694 | date = Sep 2000 | pmid = 10966831 | doi = 10.1006/jmcc.2000.1204 }} [278] => * Mutation E101K: changes of net charge and formation of a weak electrostatic link in the actomyosin-binding site. [279] => * P166A: interaction zone between actin monomers. [280] => * A333P: actin-myosin interaction zone. [281] => [282] => Pathogenesis appears to involve a compensatory mechanism: the mutated proteins act like toxins with a dominant effect, decreasing the heart's ability to [[Heart#Function|contract]] causing abnormal mechanical behaviour such that the hypertrophy, that is usually delayed, is a consequence of the cardiac muscle's normal response to [[stress (physiology)|stress]].{{cite journal | vauthors = Ramírez CD, Padrón R |title=Cardiomiopatía Hipertrófica familiar: Genes, mutaciones y modelos animales. Revisión |trans-title=Familial Hypertrophic Cardiomyopathy: genes, mutations and animal models. a review |language=es |journal=Investigación Clínica |volume=45 |issue=1 |year=2004 |pages=69–100 |url=http://ve.scielo.org/scielo.php?pid=S0535-51332004000100008&script=sci_abstract }} [283] => [284] => Recent studies have discovered ACTC1 mutations that are implicated in two other pathological processes: Infantile idiopathic [[restrictive cardiomyopathy]],{{cite journal | vauthors = Kaski JP, Syrris P, Burch M, Tomé-Esteban MT, Fenton M, Christiansen M, Andersen PS, Sebire N, Ashworth M, Deanfield JE, McKenna WJ, Elliott PM | title = Idiopathic restrictive cardiomyopathy in children is caused by mutations in cardiac sarcomere protein genes | journal = Heart | volume = 94 | issue = 11 | pages = 1478–1484 | date = Nov 2008 | pmid = 18467357 | doi = 10.1136/hrt.2007.134684 | s2cid = 44257334 }} and [[Noncompaction cardiomyopathy|noncompaction of the left ventricular myocardium]].{{cite journal | vauthors = Pigott TJ, Jefferson D | title = Idiopathic common peroneal nerve palsy--a review of thirteen cases | journal = British Journal of Neurosurgery | volume = 5 | issue = 1 | pages = 7–11 | year = 1991 | pmid = 1850600 | doi = 10.3109/02688699108998440 }} [285] => [286] => === In cytoplasmatic actins === [287] => ''[[ACTB]]'' is a highly complex [[Locus (genetics)|locus]]. A number of [[pseudogene]]s exist that are distributed throughout the [[genome]], and its sequence contains six exons that can give rise to up to 21 different transcriptions by [[alternative splicing]], which are known as the β-actins. Consistent with this complexity, its products are also found in a number of locations and they form part of a wide variety of processes ([[cytoskeleton]], NuA4 [[histone]]-acyltransferase complex, [[cell nucleus]]) and in addition they are associated with the mechanisms of a great number of pathological processes ([[Cancer|carcinomas]], juvenile [[dystonia]], infection mechanisms, [[nervous system]] malformations and tumour invasion, among others).{{cite web | url = https://www.ncbi.nlm.nih.gov/IEB/Research/Acembly/av.cgi?db=human&l=ACTB | title = Gene: ACTB | website = AceView | publisher = U.S. National Center for Biotechnology Information (NCBI) | access-date = 2013-01-21 | url-status = live | archive-url = https://web.archive.org/web/20130618060821/http://www.ncbi.nlm.nih.gov/IEB/Research/Acembly/av.cgi?db=human&l=ACTB | archive-date = 2013-06-18 }} A new form of actin has been discovered, kappa actin, which appears to substitute for β-actin in processes relating to [[tumour]]s.{{cite journal | vauthors = Chang KW, Yang PY, Lai HY, Yeh TS, Chen TC, Yeh CT | title = Identification of a novel actin isoform in hepatocellular carcinoma | journal = Hepatology Research | volume = 36 | issue = 1 | pages = 33–39 | date = Sep 2006 | pmid = 16824795 | doi = 10.1016/j.hepres.2006.05.003 }} [288] => [289] => [[File:Neuron actin cytoskeleton.JPG|left|thumb|Image taken using [[confocal microscopy]] and employing the use of specific [[Antibody|antibodies]] showing actin's cortical network. In the same way that in juvenile [[dystonia]] there is an interruption in the structures of the [[cytoskeleton]], in this case it is produced by [[cytochalasin D]].{{cite journal | vauthors = Williams KL, Rahimtula M, Mearow KM | title = Hsp27 and axonal growth in adult sensory neurons in vitro | journal = BMC Neuroscience | volume = 6 | issue = 1 | pages = 24 | year = 2005 | pmid = 15819993 | pmc = 1087488 | doi = 10.1186/1471-2202-6-24 | doi-access = free }}]] [290] => [291] => Three pathological processes have so far been discovered that are caused by a direct alteration in gene sequence: [292] => * [[Hemangiopericytoma]] with t(7;12)(p22;q13)-translocations is a rare affliction, in which a [[Mutation#By effect on structure|translocational mutation]] causes the fusion of the ''ACTB'' gene over [[GLI1]] in [[Chromosome 12 (human)|Chromosome 12]].{{cite web | url = http://atlasgeneticsoncology.org/Tumors/Pericytomt0712ID5192.html | title = Soft tissue tumors: Pericytoma with t(7;12) | publisher = University Hospital of Poitiers | website = Atlas of Genetics and Cytogenetics in Oncology and Haematology | access-date = 2013-01-21 | url-status = live | archive-url = http://archive.wikiwix.com/cache/20081230112153/http://atlasgeneticsoncology.org/Tumors/Pericytomt0712ID5192.html | archive-date = 2008-12-30 }} [293] => * Juvenile onset [[dystonia]] is a rare [[degenerative disease]] that affects the [[central nervous system]]; in particular, it affects areas of the [[neocortex]] and [[thalamus]], where rod-like [[eosinophilic]] inclusions are formed. The affected individuals represent a [[phenotype]] with deformities on the median line, sensory [[Deafness|hearing loss]] and dystonia. It is caused by a point mutation in which the amino acid [[tryptophan]] replaces [[arginine]] in position 183. This alters actin's interaction with the ADF/[[cofilin]] system, which regulates the dynamics of [[Neuron|nerve cell]] cytoskeleton formation.{{cite journal | vauthors = Procaccio V, Salazar G, Ono S, Styers ML, Gearing M, Davila A, Jimenez R, Juncos J, Gutekunst CA, Meroni G, Fontanella B, Sontag E, Sontag JM, Faundez V, Wainer BH | title = A mutation of beta -actin that alters depolymerization dynamics is associated with autosomal dominant developmental malformations, deafness, and dystonia | journal = American Journal of Human Genetics | volume = 78 | issue = 6 | pages = 947–960 | date = Jun 2006 | pmid = 16685646 | pmc = 1474101 | doi = 10.1086/504271 }} [294] => * A dominant point mutation has also been discovered that causes [[neutrophil granulocyte]] dysfunction and recurring [[infection]]s. It appears that the mutation modifies the domain responsible for binding between [[profilin]] and other regulatory proteins. Actin's affinity for profilin is greatly reduced in this allele.{{cite journal | vauthors = Nunoi H, Yamazaki T, Tsuchiya H, Kato S, Malech HL, Matsuda I, Kanegasaki S | title = A heterozygous mutation of beta-actin associated with neutrophil dysfunction and recurrent infection | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 96 | issue = 15 | pages = 8693–8698 | date = Jul 1999 | pmid = 10411937 | pmc = 17578 | doi = 10.1073/pnas.96.15.8693 | bibcode = 1999PNAS...96.8693N | doi-access = free }} [295] => [296] => The ''[[ACTG1]]'' locus codes for the cytosolic γ-actin protein that is responsible for the formation of cytoskeletal [[microfilament]]s. It contains six [[exon]]s, giving rise to 22 different [[Messenger RNA|mRNAs]], which produce four complete [[isoform]]s whose form of expression is probably dependent on the type of [[Tissue (biology)|tissue]] they are found in. It also has two different [[Promoter (genetics)|DNA promoters]].{{cite web | url = https://www.ncbi.nlm.nih.gov/IEB/Research/Acembly/av.cgi?db=human&l=ACTG1 | title = Gene: ACTG1 | website = AceView | publisher = U.S. National Center for Biotechnology Information (NCBI) | access-date = 2013-01-21 | url-status = live | archive-url = https://web.archive.org/web/20130618063217/http://www.ncbi.nlm.nih.gov/IEB/Research/Acembly/av.cgi?db=human&l=ACTG1 | archive-date = 2013-06-18 }} It has been noted that the sequences translated from this locus and from that of β-actin are very similar to the predicted ones, suggesting a common ancestral sequence that suffered duplication and genetic conversion.{{cite journal | vauthors = Erba HP, Gunning P, Kedes L | title = Nucleotide sequence of the human gamma cytoskeletal actin mRNA: anomalous evolution of vertebrate non-muscle actin genes | journal = Nucleic Acids Research | volume = 14 | issue = 13 | pages = 5275–5294 | date = Jul 1986 | pmid = 3737401 | pmc = 311540 | doi = 10.1093/nar/14.13.5275 }} [297] => [298] => In terms of pathology, it has been associated with processes such as [[amyloidosis]], [[retinitis pigmentosa]], infection mechanisms, [[kidney]] diseases, and various types of congenital hearing loss. [299] => [300] => Six autosomal-dominant point mutations in the sequence have been found to cause various types of hearing loss, particularly sensorineural hearing loss linked to the DFNA 20/26 locus. It seems that they affect the [[stereocilia]] of the ciliated cells present in the inner ear's [[Organ of Corti]]. β-actin is the most abundant protein found in human tissue, but it is not very abundant in ciliated cells, which explains the location of the pathology. On the other hand, it appears that the majority of these mutations affect the areas involved in linking with other proteins, particularly actomyosin. Some experiments have suggested that the pathological mechanism for this type of hearing loss relates to the F-actin in the mutations being more sensitive to cofilin than normal.{{cite journal | vauthors = Bryan KE, Rubenstein PA | title = Allele-specific effects of human deafness gamma-actin mutations (DFNA20/26) on the actin/cofilin interaction | journal = The Journal of Biological Chemistry | volume = 284 | issue = 27 | pages = 18260–18269 | date = Jul 2009 | pmid = 19419963 | pmc = 2709362 | doi = 10.1074/jbc.M109.015818 | doi-access = free }} [301] => [302] => However, although there is no record of any case, it is known that γ-actin is also expressed in skeletal muscles, and although it is present in small quantities, [[model organism]]s have shown that its absence can give rise to myopathies.{{cite journal | vauthors = Sonnemann KJ, Fitzsimons DP, Patel JR, Liu Y, Schneider MF, Moss RL, Ervasti JM | title = Cytoplasmic gamma-actin is not required for skeletal muscle development but its absence leads to a progressive myopathy | journal = Developmental Cell | volume = 11 | issue = 3 | pages = 387–397 | date = Sep 2006 | pmid = 16950128 | doi = 10.1016/j.devcel.2006.07.001 | doi-access = free }} [303] => [304] => === Other pathological mechanisms === [305] => Some infectious agents use actin, especially cytoplasmic actin, in their [[Alternation of generations|life cycle]]. Two basic forms are present in [[bacteria]]: [306] => * ''[[Listeria monocytogenes]]'', some species of ''[[Rickettsia]]'', ''[[Shigella flexneri]]'' and other intracellular germs escape from [[phagocytosis|phagocytic]] vacuoles by coating themselves with a capsule of actin filaments. ''L. monocytogenes'' and ''S. flexneri'' both generate a tail in the form of a "comet tail" that gives them mobility. Each species exhibits small differences in the molecular polymerization mechanism of their "comet tails". Different displacement velocities have been observed, for example, with ''Listeria'' and ''Shigella'' found to be the fastest.{{cite journal | vauthors = Gouin E, Gantelet H, Egile C, Lasa I, Ohayon H, Villiers V, Gounon P, Sansonetti PJ, Cossart P | display-authors = 6 | title = A comparative study of the actin-based motilities of the pathogenic bacteria Listeria monocytogenes, Shigella flexneri and Rickettsia conorii | journal = Journal of Cell Science | volume = 112 | issue = 11 | pages = 1697–1708 | date = June 1999 | pmid = 10318762 | doi = 10.1242/jcs.112.11.1697 }} Many experiments have demonstrated this mechanism ''in vitro''. This indicates that the bacteria are not using a myosin-like protein motor, and it appears that their propulsion is acquired from the pressure exerted by the polymerization that takes place near to the microorganism's cell wall. The bacteria have previously been surrounded by ABPs from the host, and as a minimum the covering contains [[Arp2/3 complex]], [[Ena/Vasp homology proteins|Ena/VASP proteins]], cofilin, a buffering protein and nucleation promoters, such as [[vinculin]] complex. Through these movements they form protrusions that reach the neighbouring cells, infecting them as well so that the [[immune system]] can only fight the infection through cell immunity. The movement could be caused by the modification of the curve and debranching of the filaments.{{cite journal | vauthors = Lambrechts A, Gevaert K, Cossart P, Vandekerckhove J, Van Troys M | title = Listeria comet tails: the actin-based motility machinery at work | journal = Trends in Cell Biology | volume = 18 | issue = 5 | pages = 220–227 | date = May 2008 | pmid = 18396046 | doi = 10.1016/j.tcb.2008.03.001 }} Other species, such as ''[[Mycobacterium marinum]]'' and ''[[Burkholderia pseudomallei]]'', are also capable of localized polymerization of cellular actin to aid their movement through a mechanism that is centered on the Arp2/3 complex. In addition the vaccine [[virus]] ''[[Vaccinia]]'' also uses elements of the actin cytoskeleton for its dissemination.{{cite journal | vauthors = Gouin E, Welch MD, Cossart P | title = Actin-based motility of intracellular pathogens | journal = Current Opinion in Microbiology | volume = 8 | issue = 1 | pages = 35–45 | date = Feb 2005 | pmid = 15694855 | doi = 10.1016/j.mib.2004.12.013 }} [307] => * ''[[Pseudomonas aeruginosa]]'' is able to form a protective [[biofilm]] in order to escape a [[host (biology)|host organism]]'s defences, especially [[Neutrophil granulocyte|white blood cells]] and [[Antibacterial|antibiotics]]. The biofilm is constructed using [[DNA]] and actin filaments from the host organism.{{cite journal | vauthors = Parks QM, Young RL, Poch KR, Malcolm KC, Vasil ML, Nick JA | title = Neutrophil enhancement of Pseudomonas aeruginosa biofilm development: human F-actin and DNA as targets for therapy | journal = Journal of Medical Microbiology | volume = 58 | issue = Pt 4 | pages = 492–502 | date = Apr 2009 | pmid = 19273646 | pmc = 2677169 | doi = 10.1099/jmm.0.005728-0 }} [308] => [309] => In addition to the previously cited example, actin polymerization is stimulated in the initial steps of the internalization of some viruses, notably [[HIV]], by, for example, inactivating the cofilin complex.{{cite journal | vauthors = Liu Y, Belkina NV, Shaw S | title = HIV infection of T cells: actin-in and actin-out | journal = Science Signaling | volume = 2 | issue = 66 | pages = pe23 | year = 2009 | pmid = 19366992 | doi = 10.1126/scisignal.266pe23 | s2cid = 30259258 | url = https://zenodo.org/record/1231273 }} [310] => [311] => The role that actin plays in the invasion process of cancer cells has still not been determined.{{cite journal | vauthors = Machesky LM, Tang HR | title = Actin-based protrusions: promoters or inhibitors of cancer invasion? | journal = Cancer Cell | volume = 16 | issue = 1 | pages = 5–7 | date = Jul 2009 | pmid = 19573806 | doi = 10.1016/j.ccr.2009.06.009 | doi-access = free }} [312] => [313] => ==Applications== [314] => Actin is used in scientific and technological laboratories as a track for [[molecular motor]]s such as myosin (either in muscle tissue or outside it) and as a necessary component for cellular functioning. It can also be used as a diagnostic tool, as several of its anomalous variants are related to the appearance of specific pathologies. [315] => *[[Nanotechnology]]. Actin-myosin systems act as molecular motors that permit the transport of vesicles and organelles throughout the cytoplasm. It is possible that actin could be applied to [[nanotechnology]] as its dynamic ability has been harnessed in a number of experiments including those carried out in acellular systems. The underlying idea is to use the microfilaments as tracks to guide molecular motors that can transport a given load. That is actin could be used to define a circuit along which a load can be transported in a more or less controlled and directed manner. In terms of general applications, it could be used for the directed transport of molecules for deposit in determined locations, which would permit the controlled assembly of nanostructures.{{Cite journal|vauthors=Hess H, Clemmens J, Qin D, Howard J, Vogel V | year= 2001 | title = Light-controlled molecular shuttles made from motor proteins carrying cargo on engineered surfaces | journal= Nano Letters | volume= 1 | issue= 5 | pages = 235–239 | doi = 10.1021/nl015521e | bibcode= 2001NanoL...1..235H }} These attributes could be applied to laboratory processes such as on ''[[lab-on-a-chip]]'', in nanocomponent mechanics and in nanotransformers that convert mechanical energy into electrical energy.{{Cite journal |vauthors=Mansson A, Sundberg M, Bunk R, Balaz M, Nicholls IA, Omling P, Tegenfeldt JO, Tagerud S, Montelius L | year= 2005 | title = Actin-Based Molecular Motors for Cargo Transportation in Nanotechnology—Potentials and Challenges | journal = IEEE Transactions on Advanced Packaging | volume = 28 | issue= 4 | pages = 547–555 | doi= 10.1109/TADVP.2005.858309 | s2cid= 33608087 }} [316] => [317] => [[File:Western blot for cytoplasmic actin from rat lung and epididymis.png|thumb|150px|left|Western blot for cytoplasmic actin from rat lung and epididymis]] [318] => *Actin is used as an internal control in [[western blot]]s to ascertain that equal amounts of protein have been loaded on each lane of the gel. In the blot example shown on the left side, 75 μg of total protein was loaded in each well. The blot was reacted with anti-β-actin antibody (for other details of the blot see the reference {{cite journal | vauthors = Sharma S, Hanukoglu I | title = Mapping the sites of localization of epithelial sodium channel (ENaC) and CFTR in segments of the mammalian epididymis | journal = Journal of Molecular Histology | volume = 50 | issue = 2 | pages = 141–154 | date = April 2019 | pmid = 30659401 | doi = 10.1007/s10735-019-09813-3 | s2cid = 58026884 }}) [319] => [320] => The use of actin as an internal control is based on the assumption that its expression is practically constant and independent of experimental conditions. By comparing the expression of the gene of interest to that of the actin, it is possible to obtain a relative quantity that can be compared between different experiments,{{cite journal | vauthors = Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A, Speleman F | title = Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes | journal = Genome Biology | volume = 3 | issue = 7 | pages = RESEARCH0034 | date = Jun 2002 | pmid = 12184808 | pmc = 126239 | doi = 10.1186/gb-2002-3-7-research0034 | doi-access = free }} whenever the expression of the latter is constant. It is worth pointing out that actin does not always have the desired stability in its [[gene expression]].{{cite journal | vauthors = Selvey S, Thompson EW, Matthaei K, Lea RA, Irving MG, Griffiths LR | title = Beta-actin--an unsuitable internal control for RT-PCR | journal = Molecular and Cellular Probes | volume = 15 | issue = 5 | pages = 307–311 | date = Oct 2001 | pmid = 11735303 | doi = 10.1006/mcpr.2001.0376 | url = https://github.com/JeremyMGibson/verbose-garbanzo/raw/master/62818/134000 }} [321] => *Health. Some [[allele]]s of actin cause diseases; for this reason techniques for their detection have been developed. In addition, actin can be used as an indirect marker in surgical pathology: it is possible to use variations in the pattern of its distribution in tissue as a marker of invasion in [[neoplasm|neoplasia]], [[vasculitis]], and other conditions.{{cite journal | vauthors = Mukai K, Schollmeyer JV, Rosai J | title = Immunohistochemical localization of actin: applications in surgical pathology | journal = The American Journal of Surgical Pathology | volume = 5 | issue = 1 | pages = 91–97 | date = Jan 1981 | pmid = 7018275 | doi = 10.1097/00000478-198101000-00013 }} Further, due to actin's close association with the apparatus of muscular contraction its levels in skeletal muscle diminishes when these tissues [[atrophy]], it can therefore be used as a marker of this physiological process.{{cite journal | vauthors = Haddad F, Roy RR, Zhong H, Edgerton VR, Baldwin KM | s2cid = 8268572 | title = Atrophy responses to muscle inactivity. II. Molecular markers of protein deficits | journal = Journal of Applied Physiology | volume = 95 | issue = 2 | pages = 791–802 | date = Aug 2003 | pmid = 12716877 | doi = 10.1152/japplphysiol.01113.2002 }} [322] => *[[Food technology]]. It is possible to determine the quality of certain processed foods, such as [[embutido|sausages]], by quantifying the amount of actin present in the constituent meat. Traditionally, a method has been used that is based on the detection of [[histidine|3-methylhistidine]] in [[hydrolysis|hydrolyzed]] samples of these products, as this compound is present in actin and F-myosin's heavy chain (both are major components of muscle). The generation of this compound in flesh derives from the [[methylation]] of [[histidine]] residues present in both proteins.{{cite journal | vauthors = Hocquette JF, Lehnert S, Barendse W, Cassar-Malek I, Picard B | s2cid = 86189373 | title = Current advances in proteomic analysis and its use for the resolution of poultry meat quality | journal = World's Poultry Science Journal | year= 2006 | volume= 62 | issue= 1 | pages = 123–130 | doi = 10.1079/WPS200589 }}{{cite book | vauthors = Nollet L | title = Handbook of food analysis | publisher = Marcel Dekker | location = New York, N.Y | year = 2004 | pages = 1741–2226| isbn = 978-0-8247-5039-8 | edition = 2 | volume = 3 | chapter = Methods and Instruments in Applied Food Analysis }} [323] => [324] => == History == [325] => [[File:GyorgyiNIH.jpg|thumb|[[Nobel Prize]] winning [[physiologist]] [[Albert Szent-Györgyi|Albert von Szent-Györgyi Nagyrápolt]], co-discoverer of actin with [[Brunó Ferenc Straub]]]] [326] => Actin was first observed [[experiment]]ally in 1887 by [[W.D. Halliburton]], who extracted a protein from muscle that 'coagulated' preparations of [[myosin]] that he called "myosin-ferment".{{cite journal | vauthors = Halliburton WD | title = On Muscle-Plasma | journal = The Journal of Physiology | volume = 8 | issue = 3–4 | pages = 133–202 | date = Aug 1887 | pmid = 16991477 | pmc = 1485127 | doi = 10.1113/jphysiol.1887.sp000252 }} However, Halliburton was unable to further refine his findings, and the discovery of actin is credited instead to [[Brunó Ferenc Straub]], a young [[biochemist]] working in [[Albert Szent-Györgyi]]'s laboratory at the Institute of Medical Chemistry at the [[University of Szeged]], [[Hungary]]. [327] => [328] => Following up on the discovery of [[Ilona Banga]] & Szent-Györgyi in 1941 that the coagulation only occurs in some myosin extractions and was reversed upon the addition of ATP,{{Cite journal| vauthors = Banga I |date=1942| veditors = Szent-Györgyi A |title=Preparation and properties of myosin A and B.|url=http://actin.aok.pte.hu/archives/index.php|journal=Studies from the Institute of Medical Chemistry University Szeged. 1941-1942.|volume=I|pages=5–15}} Straub identified and purified actin from those myosin preparations that did coagulate. Building on Banga's original extraction method, he developed a novel technique for [[Extraction (chemistry)|extracting]] muscle protein that allowed him to isolate substantial amounts of relatively [[chemical substance|pure]] actin, published in 1942.{{Cite journal| vauthors = Straub BF |date=1942| veditors = Szent-Györgyi A |title=Actin|url=http://actin.aok.pte.hu/archives/index.php|journal=Studies from the Institute of Medical Chemistry University Szeged. 1942.|volume=II|pages=3–15}} Straub's method is essentially the same as that used in [[laboratory|laboratories]] today. Since Straub's protein was necessary to activate the coagulation of myosin, it was dubbed ''actin''.{{cite journal | vauthors = Bugyi B, Kellermayer M | title = The discovery of actin: "to see what everyone else has seen, and to think what nobody has thought" | journal = Journal of Muscle Research and Cell Motility | volume = 41 | issue = 1 | pages = 3–9 | date = March 2020 | pmid = 31093826 | pmc = 7109165 | doi = 10.1007/s10974-019-09515-z }} Realizing that Banga's coagulating myosin preparations contained actin as well, Szent-Györgyi called the mixture of both proteins [[actomyosin]].{{Cite journal| vauthors = Szent-Györgyi A |date=1942| veditors = Szent-Györgyi A |title=Discussion|url=http://actin.aok.pte.hu/archives/index.php|journal=Studies from the Institute of Medical Chemistry University Szeged. 1941-1942.|volume=I|pages=67–71}} [329] => [330] => The hostilities of [[World War II]] meant Szent-Gyorgyi was unable to publish his lab's work in [[Western countries|Western]] [[scientific journal]]s. Actin therefore only became well known in the West in 1945, when their paper was published as a supplement to the ''Acta Physiologica Scandinavica''.{{cite journal |author =Szent-Gyorgyi A | title = Studies on muscle | journal = Acta Physiol Scandinav | volume = 9 | issue = Suppl | page = 25 | year = 1945 }} Straub continued to work on actin, and in 1950 reported that actin contains bound [[adenosine triphosphate|ATP]]{{cite journal | vauthors = Straub FB, Feuer G | title = Adenosinetriphosphate. The functional group of actin. 1950 | journal = Biochimica et Biophysica Acta | volume = 1000 | pages = 180–195 | year = 1989 | pmid = 2673365 | doi = 10.1016/0006-3002(50)90052-7 }} and that, during [[polymer]]ization of the protein into [[microfilament]]s, the [[nucleotide]] is [[hydrolysis|hydrolyzed]] to [[adenosine diphosphate|ADP]] and inorganic [[phosphate]] (which remain bound to the microfilament). Straub suggested that the transformation of ATP-bound actin to ADP-bound actin played a role in muscular contraction. In fact, this is true only in [[smooth muscle]], and was not supported through experimentation until 2001.{{cite journal | vauthors = Bárány M, Barron JT, Gu L, Bárány K | title = Exchange of the actin-bound nucleotide in intact arterial smooth muscle | journal = The Journal of Biological Chemistry | volume = 276 | issue = 51 | pages = 48398–48403 | date = December 2001 | pmid = 11602582 | doi = 10.1074/jbc.M106227200 | doi-access = free }} [331] => [332] => The [[peptide sequence|amino acid sequencing]] of actin was completed by M. Elzinga and co-workers in 1973.{{cite journal | vauthors = Elzinga M, Collins JH, Kuehl WM, Adelstein RS | title = Complete amino-acid sequence of actin of rabbit skeletal muscle | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 70 | issue = 9 | pages = 2687–2691 | date = Sep 1973 | pmid = 4517681 | pmc = 427084 | doi = 10.1073/pnas.70.9.2687 | bibcode = 1973PNAS...70.2687E | doi-access = free }} The [[X-ray crystallography|crystal structure]] of G-actin was solved in 1990 by Kabsch and colleagues.{{cite journal | vauthors = Kabsch W, Mannherz HG, Suck D, Pai EF, Holmes KC | title = Atomic structure of the actin:DNase I complex | journal = Nature | volume = 347 | issue = 6288 | pages = 37–44 | date = Sep 1990 | pmid = 2395459 | doi = 10.1038/347037a0 | bibcode = 1990Natur.347...37K | s2cid = 925337 }} In the same year, a model for F-actin was proposed by Holmes and colleagues following experiments using co-crystallization with different proteins. The procedure of co-crystallization with different proteins was used repeatedly during the following years, until in 2001 the isolated protein was crystallized along with ADP. However, there is still no high-resolution X-ray structure of F-actin. The crystallization of G-actin was possible due to the use of a [[rhodamine]] conjugate that impedes polymerization by blocking the amino acid [[Cysteine|cys-374]].{{PDB|1J6Z}}; {{cite journal | vauthors = Otterbein LR, Graceffa P, Dominguez R | s2cid = 12030018 | title = The crystal structure of uncomplexed actin in the ADP state | journal = Science | volume = 293 | issue = 5530 | pages = 708–711 | date = Jul 2001 | pmid = 11474115 | doi = 10.1126/science.1059700 }} Christine Oriol-Audit died in the same year that actin was first crystallized but she was the researcher that in 1977 first crystallized actin in the absence of Actin Binding Proteins (ABPs). However, the resulting crystals were too small for the available technology of the time.{{cite journal | vauthors = Oriol C, Dubord C, Landon F | title = Crystallization of native striated-muscle actin | journal = FEBS Letters | volume = 73 | issue = 1 | pages = 89–91 | date = Jan 1977 | pmid = 320040 | doi = 10.1016/0014-5793(77)80022-7 | s2cid = 5142918 | doi-access = free }} [333] => [334] => Although no high-resolution model of actin's filamentous form currently exists, in 2008 Sawaya's team were able to produce a more exact model of its structure based on multiple crystals of actin [[Dimer (chemistry)|dimers]] that bind in different places.{{cite journal | vauthors = Sawaya MR, Kudryashov DS, Pashkov I, Adisetiyo H, Reisler E, Yeates TO | title = Multiple crystal structures of actin dimers and their implications for interactions in the actin filament | journal = Acta Crystallographica Section D | volume = 64 | issue = Pt 4 | pages = 454–465 | date = Apr 2008 | pmid = 18391412 | pmc = 2631129 | doi = 10.1107/S0907444908003351 | bibcode = 2008AcCrD..64..454S }} This model has subsequently been further refined by Sawaya and Lorenz. Other approaches such as the use of [[cryo-electron microscopy]] and [[synchrotron radiation]] have recently allowed increasing resolution and better understanding of the nature of the interactions and conformational changes implicated in the formation of actin filaments.{{cite journal | vauthors = Narita A, Takeda S, Yamashita A, Maéda Y | title = Structural basis of actin filament capping at the barbed-end: a cryo-electron microscopy study | journal = The EMBO Journal | volume = 25 | issue = 23 | pages = 5626–5633 | date = Nov 2006 | pmid = 17110933 | pmc = 1679762 | doi = 10.1038/sj.emboj.7601395 }}{{cite journal | vauthors = Oda T, Iwasa M, Aihara T, Maéda Y, Narita A | title = The nature of the globular- to fibrous-actin transition | journal = Nature | volume = 457 | issue = 7228 | pages = 441–445 | date = Jan 2009 | pmid = 19158791 | doi = 10.1038/nature07685 | bibcode = 2009Natur.457..441O | s2cid = 4317892 }}{{cite journal | vauthors = von der Ecken J, Müller M, Lehman W, Manstein DJ, Penczek PA, Raunser S | title = Structure of the F-actin-tropomyosin complex | journal = Nature | volume = 519 | issue = 7541 | pages = 114–117 | date = May 2015 | pmid = 25470062 | pmc = 4477711 | doi = 10.1038/nature14033 | bibcode = 2015Natur.519..114V }} [335] => [336] => == Research == [337] => === Chemical inhibitors === [338] => [[File:Skeletal formula of phalloidin.svg|thumb|Chemical structure of [[phalloidin]]]] [339] => [340] => A number of natural [[toxin]]s that interfere with actin's dynamics are widely used in research to study actin's role in biology. [[Latrunculin]] – a toxin produced by [[sponge]]s – binds to G-actin preventing it from joining microfilaments.{{sfn|Lodish|Berk|Kaiser|Krieger|2016|pp=791–792}} [[Cytochalasin D]] – produced by certain [[fungi]] – serves as a capping factor, binding to the (+) end of a filament and preventing further addition of actin molecules.{{sfn|Lodish|Berk|Kaiser|Krieger|2016|pp=791–792}} In contrast, the sponge toxin [[jasplakinolide]] promotes the nucleation of new actin filaments by binding and stabilzing pairs of actin molecules.{{sfn|Lodish|Berk|Kaiser|Krieger|2016|pp=792}} [[Phalloidin]] – from the "death cap" mushroom ''[[Amanita phalloides]]'' – binds to adjacent actin molecules within the F-actin filament, stabilizing the filament and preventing its depolymerization.{{sfn|Lodish|Berk|Kaiser|Krieger|2016|pp=792}} [341] => [342] => Phalloidin is often labelled with [[Fluorophore|fluorescent dyes]] to visualize actin filaments by [[fluorescence microscopy]].{{sfn|Lodish|Berk|Kaiser|Krieger|2016|pp=792}} [343] => [344] => == See also == [345] => {{Div col|colwidth=30em}} [346] => * [[Actin remodeling]] — effect on cell structure and shape [347] => * [[Active matter]] [348] => * [[Filopodia]] [349] => * [[Intermediate filament]] [350] => * [[Lamellipodium]] [351] => * [[Motor protein]] — converts chemical energy into mechanical work [352] => * [[Neuron]] [353] => * [[Phallotoxin]] [354] => {{Div col end}} [355] => [356] => == References == [357] => {{Reflist}} [358] => [359] => === Works cited === [360] => {{refbegin}} [361] => *{{cite book | vauthors = Lodish HF, Berk A, Kaiser C, Krieger M, Bretscher A, Ploegh H, Amon A, Martin KC, Darnell JE | display-authors = 6 | title = Molecular Cell Biology | date = 2016 | publisher = W.H. Freeman | location = New York | isbn = 978-1-4641-8339-3 | edition = Eighth |chapter = Cell Organization and Movement I: Microfilaments }} [362] => *{{cite journal |vauthors=Pollard TD |title=Actin and Actin-Binding Proteins |journal=Cold Spring Harb Perspect Biol |volume=8 |issue=8 |pages= a018226|date=August 2016 |pmid=26988969 |pmc=4968159 |doi=10.1101/cshperspect.a018226}} [363] => {{refend}} [364] => [365] => == External links == [366] => * [http://www.cytoskeleton.com/actin-staining-techniques Actin Staining Techniques (Live and Fixed Cell Staining)] [367] => * {{ELM|LIG_Actin_RPEL_3}} [368] => * {{ELM|LIG_Actin_WH2_1}} [369] => * {{ELM|LIG_Actin_WH2_2}} [370] => * [http://www.pdbe.org/emsearch/actin* 3D macromolecular structures of actin filaments from the EM Data Bank(EMDB)] [371] => [372] => {{Cytoskeletal proteins}} [373] => {{Muscle tissue}} [374] => {{Autoantigens}} [375] => {{Authority control}} [376] => [377] => [[Category:Autoantigens]] [378] => [[Category:Cytoskeleton proteins]] [379] => [[Category:Articles containing video clips]] [] => )
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Actin

Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of over 100 μM; its mass is roughly 42 kDa, with a diameter of 4 to 7 nm.

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