Alpha-actinin-2 explained

Alpha-actinin-2 is a protein which in humans is encoded by the ACTN2 gene.^[1] This gene encodes an alpha-actinin isoform that is expressed in both skeletal and cardiac muscles and functions to anchor myofibrillar actin thin filaments and titin to Z-discs.

Structure

Alpha-actinin-2 is a 103.8 kDa protein composed of 894 amino acids.^{[2] [3]} Each molecule is rod-shaped (35 nm in length) and it homodimerizes in an anti-parallel fashion. Each monomer has an N-terminal actin-binding region composed of two calponin homology domains, two C-terminal EF hand domains, and four tandem spectrin-like repeats form the rod domain in the central region of the molecule.^[4] The high-resolution crystal structure of human alpha-actinin 2 at 3.5 Å was recently resolved.^[5] Alpha actinins belong to the spectrin gene superfamily which represents a diverse group of actin-binding cytoskeletal proteins, including spectrin, dystrophin, utrophin and fimbrin.^{[6] [8]} DLG1,^[6] DISC1,^[9] MYOZ1,^[10] GRIN2B,^[11] ADAM12, ^[12] ACTN3,^[13] MYPN,^[14] PDLIM3,^[15] PKN,^[16] MYOT,^[17] TTN,^[18] NMDAR,^[19] SYNPO2,^[20] LDB3,^[21] and FATZ.^[10]

Function

The primary function of alpha-actinin-2 is to crosslink filamentous actin molecules and titin molecules from adjoining sarcomeres at Z-discs, a function that is modulated by phospholipids.^{[22] [23]} It is clear from studies by Hampton et al. that this crosslinking can assume a variety of conformations, with preferences for 60° and 120° angles.^[24] Alpha-actinin-2 also functions in docking signalling molecules at Z-discs, and additional studies have also implicated alpha-actinin-2 in the binding of cardiac ion channels, K_v1.5 in particular.^[6]

Clinical significance

Mutations in ACTN2 are associated with hypertrophic cardiomyopathy,^[25] as well as dilated cardiomyopathy and endocardial fibroelastosis.^[26] The diverse functions of alpha-actinin-2 are reflected in the diverse clinical presentation of patients carrying ACTN2 mutations.^[27]

Further reading

• Faulkner G, Lanfranchi G, Valle G . Telethonin and other new proteins of the Z-disc of skeletal muscle . IUBMB Life . 51 . 5 . 275–82 . May 2001 . 11699871 . 10.1080/152165401317190761 . 23688131 .
• Beggs AH, Byers TJ, Knoll JH, Boyce FM, Bruns GA, Kunkel LM . Cloning and characterization of two human skeletal muscle alpha-actinin genes located on chromosomes 1 and 11 . The Journal of Biological Chemistry . 267 . 13 . 9281–8 . May 1992 . 10.1016/S0021-9258(19)50420-3 . 1339456 . free .
• Beggs AH, Phillips HA, Kozman H, Mulley JC, Wilton SD, Kunkel LM, Laing NG . A (CA)n repeat polymorphism for the human skeletal muscle alpha-actinin gene ACTN2 and its localization on the linkage map of chromosome 1 . Genomics . 13 . 4 . 1314–5 . August 1992 . 1505962 . 10.1016/0888-7543(92)90054-V .
• Yürüker B, Niggli V . Alpha-actinin and vinculin in human neutrophils: reorganization during adhesion and relation to the actin network . Journal of Cell Science . 101 . 2 . 403–14 . February 1992 . 10.1242/jcs.101.2.403 . 1629252 .
• Pavalko FM, LaRoche SM . Activation of human neutrophils induces an interaction between the integrin beta 2-subunit (CD18) and the actin binding protein alpha-actinin . Journal of Immunology . 151 . 7 . 3795–807 . October 1993 . 10.4049/jimmunol.151.7.3795 . 8104223 . 32574143 . free .
• Yoshida M, Westlin WF, Wang N, Ingber DE, Rosenzweig A, Resnick N, Gimbrone MA . Leukocyte adhesion to vascular endothelium induces E-selectin linkage to the actin cytoskeleton . The Journal of Cell Biology . 133 . 2 . 445–55 . April 1996 . 8609175 . 2120789 . 10.1083/jcb.133.2.445 .
• Wyszynski M, Lin J, Rao A, Nigh E, Beggs AH, Craig AM, Sheng M . Competitive binding of alpha-actinin and calmodulin to the NMDA receptor . Nature . 385 . 6615 . 439–42 . January 1997 . 9009191 . 10.1038/385439a0 . 1997Natur.385..439W . 4266742 .
• Mukai H, Toshimori M, Shibata H, Takanaga H, Kitagawa M, Miyahara M, Shimakawa M, Ono Y . Interaction of PKN with alpha-actinin . The Journal of Biological Chemistry . 272 . 8 . 4740–6 . February 1997 . 9030526 . 10.1074/jbc.272.8.4740 . free .
• Young P, Ferguson C, Bañuelos S, Gautel M . Molecular structure of the sarcomeric Z-disk: two types of titin interactions lead to an asymmetrical sorting of alpha-actinin . The EMBO Journal . 17 . 6 . 1614–24 . March 1998 . 9501083 . 1170509 . 10.1093/emboj/17.6.1614 .
• Zhang S, Ehlers MD, Bernhardt JP, Su CT, Huganir RL . Calmodulin mediates calcium-dependent inactivation of N-methyl-D-aspartate receptors . Neuron . 21 . 2 . 443–53 . August 1998 . 9728925 . 10.1016/S0896-6273(00)80553-X . 18234477 . free .
• Krupp JJ, Vissel B, Thomas CG, Heinemann SF, Westbrook GL . Interactions of calmodulin and alpha-actinin with the NR1 subunit modulate Ca2+-dependent inactivation of NMDA receptors . The Journal of Neuroscience . 19 . 4 . 1165–78 . February 1999 . 9952395 . 10.1523/JNEUROSCI.19-04-01165.1999. 6786025 . free .
• Zhou Q, Ruiz-Lozano P, Martone ME, Chen J . Cypher, a striated muscle-restricted PDZ and LIM domain-containing protein, binds to alpha-actinin-2 and protein kinase C . The Journal of Biological Chemistry . 274 . 28 . 19807–13 . July 1999 . 10391924 . 10.1074/jbc.274.28.19807 . free .
• Faulkner G, Pallavicini A, Formentin E, Comelli A, Ievolella C, Trevisan S, Bortoletto G, Scannapieco P, Salamon M, Mouly V, Valle G, Lanfranchi G . ZASP: a new Z-band alternatively spliced PDZ-motif protein . The Journal of Cell Biology . 146 . 2 . 465–75 . July 1999 . 10427098 . 3206570 . 10.1083/jcb.146.2.465 .
• Tiso N, Majetti M, Stanchi F, Rampazzo A, Zimbello R, Nava A, Danieli GA . Fine mapping and genomic structure of ACTN2, the human gene coding for the sarcomeric isoform of alpha-actinin-2, expressed in skeletal and cardiac muscle . Biochemical and Biophysical Research Communications . 265 . 1 . 256–9 . November 1999 . 10548523 . 10.1006/bbrc.1999.1661 .
• Nikolopoulos SN, Spengler BA, Kisselbach K, Evans AE, Biedler JL, Ross RA . The human non-muscle alpha-actinin protein encoded by the ACTN4 gene suppresses tumorigenicity of human neuroblastoma cells . Oncogene . 19 . 3 . 380–6 . January 2000 . 10656685 . 10.1038/sj.onc.1203310 . free .
• Galliano MF, Huet C, Frygelius J, Polgren A, Wewer UM, Engvall E . Binding of ADAM12, a marker of skeletal muscle regeneration, to the muscle-specific actin-binding protein, alpha -actinin-2, is required for myoblast fusion . The Journal of Biological Chemistry . 275 . 18 . 13933–9 . May 2000 . 10788519 . 10.1074/jbc.275.18.13933 . free .
• Maruoka ND, Steele DF, Au BP, Dan P, Zhang X, Moore ED, Fedida D . alpha-actinin-2 couples to cardiac Kv1.5 channels, regulating current density and channel localization in HEK cells . FEBS Letters . 473 . 2 . 188–94 . May 2000 . 10812072 . 10.1016/S0014-5793(00)01521-0 . free .
• Kotaka M, Kostin S, Ngai S, Chan K, Lau Y, Lee SM, Li H, Ng EK, Schaper J, Tsui SK, Fung K, Lee C, Waye MM . Interaction of hCLIM1, an enigma family protein, with alpha-actinin 2 . Journal of Cellular Biochemistry . 78 . 4 . 558–65 . June 2000 . 10861853 . 10.1002/1097-4644(20000915)78:4<558::AID-JCB5>3.0.CO;2-I . 84122657 .
• Parast MM, Otey CA . Characterization of palladin, a novel protein localized to stress fibers and cell adhesions . The Journal of Cell Biology . 150 . 3 . 643–56 . August 2000 . 10931874 . 2175193 . 10.1083/jcb.150.3.643 .
• Faulkner G, Pallavicini A, Comelli A, Salamon M, Bortoletto G, Ievolella C, Trevisan S, Kojic' S, Dalla Vecchia F, Laveder P, Valle G, Lanfranchi G . FATZ, a filamin-, actinin-, and telethonin-binding protein of the Z-disc of skeletal muscle . The Journal of Biological Chemistry . 275 . 52 . 41234–42 . December 2000 . 10984498 . 10.1074/jbc.M007493200 . free .

External links

• Mass spectrometry characterization of human ACTN2 at COPaKB
• GeneReviews/NIH/NCBI/UW entry on Familial Hypertrophic Cardiomyopathy Overview

Notes and References

1. Web site: Entrez Gene: ACTN2 actinin, alpha 2.
2. Web site: Protein Information – Basic Information: Protein COPaKB ID: P35609. Cardiac Organellar Protein Atlas Knowledgebase. 2015-04-13. https://web.archive.org/web/20150413193126/http://www.heartproteome.org/copa/ProteinInfo.aspx?QType=Protein%20ID&QValue=P35609. 2015-04-13. dead.
3. Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS, Deng N, Kim AK, Choi JH, Zelaya I, Liem D, Meyer D, Odeberg J, Fang C, Lu HJ, Xu T, Weiss J, Duan H, Uhlen M, Yates JR, Apweiler R, Ge J, Hermjakob H, Ping P . Integration of cardiac proteome biology and medicine by a specialized knowledgebase . Circulation Research . 113 . 9 . 1043–53 . October 2013 . 23965338 . 4076475 . 10.1161/CIRCRESAHA.113.301151 .
4. Luther PK . The vertebrate muscle Z-disc: sarcomere anchor for structure and signalling . Journal of Muscle Research and Cell Motility . 30 . 5–6 . 171–85 . 2009 . 19830582 . 2799012 . 10.1007/s10974-009-9189-6 .
5. Ribeiro Ede A, Pinotsis N, Ghisleni A, Salmazo A, Konarev PV, Kostan J, Sjöblom B, Schreiner C, Polyansky AA, Gkougkoulia EA, Holt MR, Aachmann FL, Zagrović B, Bordignon E, Pirker KF, Svergun DI, Gautel M, Djinović-Carugo K . The structure and regulation of human muscle α-actinin . Cell . 159 . 6 . 1447–60 . December 2014 . 25433700 . 4259493 . 10.1016/j.cell.2014.10.056 .
6. Eldstrom J, Choi WS, Steele DF, Fedida D . SAP97 increases Kv1.5 currents through an indirect N-terminal mechanism . FEBS Letters . 547 . 1–3 . 205–11 . July 2003 . 12860415 . 10.1016/S0014-5793(03)00668-9 . 34857270 .
7. Skeletal, cardiac, and smooth muscle isoforms are localized to the Z-disc and analogous dense bodies, where they help anchor the myofibrillar actin filaments. Alpha-actinin 2 has been shown to interact with KCNA5,^[6]
8. Maruoka ND, Steele DF, Au BP, Dan P, Zhang X, Moore ED, Fedida D . alpha-actinin-2 couples to cardiac Kv1.5 channels, regulating current density and channel localization in HEK cells . FEBS Letters . 473 . 2 . 188–94 . May 2000 . 10812072 . 10.1016/S0014-5793(00)01521-0 . free .
9. Morris JA, Kandpal G, Ma L, Austin CP . DISC1 (Disrupted-In-Schizophrenia 1) is a centrosome-associated protein that interacts with MAP1A, MIPT3, ATF4/5 and NUDEL: regulation and loss of interaction with mutation . Human Molecular Genetics . 12 . 13 . 1591–608 . July 2003 . 12812986 . 10.1093/hmg/ddg162 .
10. Faulkner G, Pallavicini A, Comelli A, Salamon M, Bortoletto G, Ievolella C, Trevisan S, Kojic' S, Dalla Vecchia F, Laveder P, Valle G, Lanfranchi G . FATZ, a filamin-, actinin-, and telethonin-binding protein of the Z-disc of skeletal muscle . The Journal of Biological Chemistry . 275 . 52 . 41234–42 . December 2000 . 10984498 . 10.1074/jbc.M007493200 . free .
11. Wyszynski M, Lin J, Rao A, Nigh E, Beggs AH, Craig AM, Sheng M . Competitive binding of alpha-actinin and calmodulin to the NMDA receptor . Nature . 385 . 6615 . 439–42 . January 1997 . 9009191 . 10.1038/385439a0 . 1997Natur.385..439W . 4266742 .
12. Galliano MF, Huet C, Frygelius J, Polgren A, Wewer UM, Engvall E . Binding of ADAM12, a marker of skeletal muscle regeneration, to the muscle-specific actin-binding protein, alpha -actinin-2, is required for myoblast fusion . The Journal of Biological Chemistry . 275 . 18 . 13933–9 . May 2000 . 10788519 . 10.1074/jbc.275.18.13933 . free .
13. Chan Y, Tong HQ, Beggs AH, Kunkel LM . Human skeletal muscle-specific alpha-actinin-2 and -3 isoforms form homodimers and heterodimers in vitro and in vivo . Biochemical and Biophysical Research Communications . 248 . 1 . 134–9 . July 1998 . 9675099 . 10.1006/bbrc.1998.8920 .
14. Bang ML, Mudry RE, McElhinny AS, Trombitás K, Geach AJ, Yamasaki R, Sorimachi H, Granzier H, Gregorio CC, Labeit S . Myopalladin, a novel 145-kilodalton sarcomeric protein with multiple roles in Z-disc and I-band protein assemblies . The Journal of Cell Biology . 153 . 2 . 413–27 . April 2001 . 11309420 . 2169455 . 10.1083/jcb.153.2.413 .
15. Pomiès P, Macalma T, Beckerle MC . Purification and characterization of an alpha-actinin-binding PDZ-LIM protein that is up-regulated during muscle differentiation . The Journal of Biological Chemistry . 274 . 41 . 29242–50 . October 1999 . 10506181 . 10.1074/jbc.274.41.29242 . free .
16. Mukai H, Toshimori M, Shibata H, Takanaga H, Kitagawa M, Miyahara M, Shimakawa M, Ono Y . Interaction of PKN with alpha-actinin . The Journal of Biological Chemistry . 272 . 8 . 4740–6 . February 1997 . 9030526 . 10.1074/jbc.272.8.4740 . free .
17. Salmikangas P, Mykkänen OM, Grönholm M, Heiska L, Kere J, Carpén O . Myotilin, a novel sarcomeric protein with two Ig-like domains, is encoded by a candidate gene for limb-girdle muscular dystrophy . Human Molecular Genetics . 8 . 7 . 1329–36 . July 1999 . 10369880 . 10.1093/hmg/8.7.1329 . free .
18. Young P, Ferguson C, Bañuelos S, Gautel M . Molecular structure of the sarcomeric Z-disk: two types of titin interactions lead to an asymmetrical sorting of alpha-actinin . The EMBO Journal . 17 . 6 . 1614–24 . March 1998 . 9501083 . 1170509 . 10.1093/emboj/17.6.1614 .
19. Chunn CJ, Starr PR, Gilbert DN . Neutrophil toxicity of amphotericin B . Antimicrobial Agents and Chemotherapy . 12 . 2 . 226–30 . August 1977 . 900919 . 429889 . 10.1128/aac.12.2.226 .
20. Linnemann A, van der Ven PF, Vakeel P, Albinus B, Simonis D, Bendas G, Schenk JA, Micheel B, Kley RA, Fürst DO . The sarcomeric Z-disc component myopodin is a multiadapter protein that interacts with filamin and alpha-actinin . European Journal of Cell Biology . 89 . 9 . 681–92 . September 2010 . 20554076 . 10.1016/j.ejcb.2010.04.004 .
21. Jani K, Schöck F . Zasp is required for the assembly of functional integrin adhesion sites . The Journal of Cell Biology . 179 . 7 . 1583–97 . December 2007 . 18166658 . 2373490 . 10.1083/jcb.200707045 .
22. Young P, Gautel M . The interaction of titin and alpha-actinin is controlled by a phospholipid-regulated intramolecular pseudoligand mechanism . The EMBO Journal . 19 . 23 . 6331–40 . December 2000 . 11101506 . 305858 . 10.1093/emboj/19.23.6331 .
23. Fukami K, Furuhashi K, Inagaki M, Endo T, Hatano S, Takenawa T . Requirement of phosphatidylinositol 4,5-bisphosphate for alpha-actinin function . Nature . 359 . 6391 . 150–2 . September 1992 . 1326084 . 10.1038/359150a0 . 1992Natur.359..150F . 4372960 .
24. Hampton CM, Taylor DW, Taylor KA . Novel structures for alpha-actinin:F-actin interactions and their implications for actin-membrane attachment and tension sensing in the cytoskeleton . Journal of Molecular Biology . 368 . 1 . 92–104 . April 2007 . 17331538 . 1919418 . 10.1016/j.jmb.2007.01.071 .
25. Chiu C, Bagnall RD, Ingles J, Yeates L, Kennerson M, Donald JA, Jormakka M, Lind JM, Semsarian C . Mutations in alpha-actinin-2 cause hypertrophic cardiomyopathy: a genome-wide analysis . Journal of the American College of Cardiology . 55 . 11 . 1127–35 . March 2010 . 20022194 . 10.1016/j.jacc.2009.11.016 . 116513873 .
26. Mohapatra B, Jimenez S, Lin JH, Bowles KR, Coveler KJ, Marx JG, Chrisco MA, Murphy RT, Lurie PR, Schwartz RJ, Elliott PM, Vatta M, McKenna W, Towbin JA, Bowles NE . Mutations in the muscle LIM protein and alpha-actinin-2 genes in dilated cardiomyopathy and endocardial fibroelastosis . Molecular Genetics and Metabolism . 80 . 1–2 . 207–15 . 2003 . 14567970 . 10.1016/s1096-7192(03)00142-2 .
27. Bagnall RD, Molloy LK, Kalman JM, Semsarian C . Exome sequencing identifies a mutation in the ACTN2 gene in a family with idiopathic ventricular fibrillation, left ventricular noncompaction, and sudden death . BMC Medical Genetics . 15 . 1 . 99 . September 2014 . 25224718 . 10.1186/s12881-014-0099-0 . 4355500 . free .