MYOT explained

Myotilin is a protein that in humans is encoded by the MYOT gene.^{[1] [2] [3]} Myotilin (myofibrillar titin-like protein) also known as TTID (TiTin Immunoglobulin Domain) is a muscle protein that is found within the Z-disc of sarcomeres.

Structure

Myotilin is a 55.3 kDa protein composed of 496 amino acids.^[4] Myotilin was originally identified as a novel alpha-actinin binding partner with two Ig-like domains, that localized to the Z-disc.^[5] The I-type Ig-like domains reside at the C-terminal half, and are most homologous to Ig domains 2-3 of palladin and Ig domains 4-5 of myopalladin and more distantly related to Z-disc Ig domains 7 and 8 of titin. The C-terminal region hosts the binding sites for Z-band proteins, and 2 Ig domains are the site of homodimerization for myotilin.^[6] By contrast, the N-terminal part of myotilin is unique, consisting of a serine-rich region with no homology to known proteins. Several disease-associated mutations involve serine residues within the serine-rich domain.^[7] Myotilin expression in human tissues is mainly restricted to striated muscles and nerves. In muscles, myotilin is predominantly found within the Z-discs. Myotilin forms homodimers and binds alpha-actinin, actin,^[8] Filamin C,^[9] FATZ-1, FATZ-2^[10] and ZASP.^[11]

Function

Myotilin is a structural protein that, along with titin and alpha-actinin give structural integrity to sarcomeres at Z-discs in striated muscle. Myotilin induces the formation of actin bundles in vitro and in non-muscle cells. A ternary complex myotilin/actin/alpha-actinin can be observed in vitro and actin bundles formed under these conditions appear more tightly packed than those induced by alpha-actinin alone. It was demonstrated that myotilin stabilizes F-actin by slowing down the disassembly rate. Ectopic overexpression of truncated myotilin causes the disruption of nascent myofibrils and the co-accumulation of myotilin and titin in amorphous cytoplasmic precipitates. In mature sarcomeres, wild-type myotilin colocalizes with alpha-actinin and Z-disc titin, showing the striated pattern typical of sarcomeric proteins. Targeted disruption of the myotilin gene in mice does not cause significant alterations in muscle function.^[12] On the other hand, transgenic mice with mutated myotilin develop muscle dystrophy.^[13]

Clinical significance

Myotilin is mutated in various forms of muscular dystrophy: Limb-Girdle Muscular Dystrophy type 1A (LGMD1A), Myofibrillar Myopathy (MFM), Spheroid Body Myopathy and Distal Myopath.^[7] The mechanism underlying the pathology is still under investigation. It has been shown that actin binding properties of myotilin housing pathogenic mutations (Ser55Phe, Thr57Ile, Ser60Cys, and Ser95Ile) are normal,^[14] albeit with a slower rate of degradation.^[15] Surprisingly, YFP-fusion constructs of myotilin mutants (Ser55Phe, Ser55Ile, Thr57Ile, Ser60Cys, Ser60Phe, Ser95Ile, Arg405Lys) localized normally to Z-discs and exhibited normal dynamics in muscle cells.^[16]

Further reading

• Speer MC, Yamaoka LH, Gilchrist JH, Gaskell CP, Stajich JM, Vance JM, Kazantsev A, Lastra AA, Haynes CS, Beckmann JS . Confirmation of genetic heterogeneity in limb-girdle muscular dystrophy: linkage of an autosomal dominant form to chromosome 5q . American Journal of Human Genetics . 50 . 6 . 1211–7 . Jun 1992 . 1598902 . 1682558 .
• Dixon MJ, Read AP, Donnai D, Colley A, Dixon J, Williamson R . The gene for Treacher Collins syndrome maps to the long arm of chromosome 5 . American Journal of Human Genetics . 49 . 1 . 17–22 . Jul 1991 . 1676560 . 1683211 .
• Bartoloni L, Horrigan SK, Viles KD, Gilchrist JM, Stajich JM, Vance JM, Yamaoka LH, Pericak-Vance MA, Westbrook CA, Speer MC . Use of a CEPH meiotic breakpoint panel to refine the locus of limb-girdle muscular dystrophy type 1A (LGMD1A) to a 2-Mb interval on 5q31 . Genomics . 54 . 2 . 250–5 . Dec 1998 . 9828127 . 10.1006/geno.1998.5579 .
• Hauser MA, Horrigan SK, Salmikangas P, Torian UM, Viles KD, Dancel R, Tim RW, Taivainen A, Bartoloni L, Gilchrist JM, Stajich JM, Gaskell PC, Gilbert JR, Vance JM, Pericak-Vance MA, Carpen O, Westbrook CA, Speer MC . Myotilin is mutated in limb girdle muscular dystrophy 1A . Human Molecular Genetics . 9 . 14 . 2141–7 . Sep 2000 . 10958653 . 10.1093/hmg/9.14.2141 . free .
• van der Ven PF, Wiesner S, Salmikangas P, Auerbach D, Himmel M, Kempa S, Hayess K, Pacholsky D, Taivainen A, Schröder R, Carpén O, Fürst DO . Indications for a novel muscular dystrophy pathway. gamma-filamin, the muscle-specific filamin isoform, interacts with myotilin . The Journal of Cell Biology . 151 . 2 . 235–48 . Oct 2000 . 11038172 . 2192634 . 10.1083/jcb.151.2.235 .
• Hauser MA, Conde CB, Kowaljow V, Zeppa G, Taratuto AL, Torian UM, Vance J, Pericak-Vance MA, Speer MC, Rosa AL . myotilin Mutation found in second pedigree with LGMD1A . American Journal of Human Genetics . 71 . 6 . 1428–32 . Dec 2002 . 12428213 . 378586 . 10.1086/344532 .
• Salmikangas P, van der Ven PF, Lalowski M, Taivainen A, Zhao F, Suila H, Schröder R, Lappalainen P, Fürst DO, Carpén O . Myotilin, the limb-girdle muscular dystrophy 1A (LGMD1A) protein, cross-links actin filaments and controls sarcomere assembly . Human Molecular Genetics . 12 . 2 . 189–203 . Jan 2003 . 12499399 . 10.1093/hmg/ddg020 . free .
• Battle MA, Maher VM, McCormick JJ . ST7 is a novel low-density lipoprotein receptor-related protein (LRP) with a cytoplasmic tail that interacts with proteins related to signal transduction pathways . Biochemistry . 42 . 24 . 7270–82 . Jun 2003 . 12809483 . 10.1021/bi034081y .
• Selcen D, Engel AG . Mutations in myotilin cause myofibrillar myopathy . Neurology . 62 . 8 . 1363–71 . Apr 2004 . 15111675 . 10.1212/01.wnl.0000123576.74801.75 . 23068161 .
• Witt SH, Granzier H, Witt CC, Labeit S . MURF-1 and MURF-2 target a specific subset of myofibrillar proteins redundantly: towards understanding MURF-dependent muscle ubiquitination . Journal of Molecular Biology . 350 . 4 . 713–22 . Jul 2005 . 15967462 . 10.1016/j.jmb.2005.05.021 .
• Gontier Y, Taivainen A, Fontao L, Sonnenberg A, van der Flier A, Carpen O, Faulkner G, Borradori L . The Z-disc proteins myotilin and FATZ-1 interact with each other and are connected to the sarcolemma via muscle-specific filamins . Journal of Cell Science . 118 . Pt 16 . 3739–49 . Aug 2005 . 16076904 . 10.1242/jcs.02484 . free .
• von Nandelstadh P, Grönholm M, Moza M, Lamberg A, Savilahti H, Carpén O . Actin-organising properties of the muscular dystrophy protein myotilin . Experimental Cell Research . 310 . 1 . 131–9 . Oct 2005 . 16122733 . 10.1016/j.yexcr.2005.06.027 .
• Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M . Towards a proteome-scale map of the human protein-protein interaction network . Nature . 437 . 7062 . 1173–8 . Oct 2005 . 16189514 . 10.1038/nature04209 . 2005Natur.437.1173R . 4427026 .
• Foroud T, Pankratz N, Batchman AP, Pauciulo MW, Vidal R, Miravalle L, Goebel HH, Cushman LJ, Azzarelli B, Horak H, Farlow M, Nichols WC . A mutation in myotilin causes spheroid body myopathy . Neurology . 65 . 12 . 1936–40 . Dec 2005 . 16380616 . 10.1212/01.wnl.0000188872.28149.9a . 9593230 .
• Garvey SM, Senderek J, Beckmann JS, Seboun E, Jackson CE, Hauser MA . Myotilin is not the causative gene for vocal cord and pharyngeal weakness with distal myopathy (VCPDM) . Annals of Human Genetics . 70 . Pt 3 . 414–6 . May 2006 . 16674563 . 10.1111/j.1529-8817.2005.00252.x . 26853063 .
• Pénisson-Besnier I, Talvinen K, Dumez C, Vihola A, Dubas F, Fardeau M, Hackman P, Carpen O, Udd B . Myotilinopathy in a family with late onset myopathy . Neuromuscular Disorders . 16 . 7 . 427–31 . Jul 2006 . 16793270 . 10.1016/j.nmd.2006.04.009 . 21589529 .

External links

• 10.1161/CIRCRESAHA.113.301151 . 23965338 . 4076475 . 113 . 9 . Integration of cardiac proteome biology and medicine by a specialized knowledgebase. . Oct 2013 . Circ Res . 1043–53 . 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.
• GeneReviews/NIH/NCBI/UW entry on Myofibrillar Myopathy

Notes and References

1. Godley LA, Lai F, Liu J, Zhao N, Le Beau MM . TTID: A novel gene at 5q31 encoding a protein with titin-like features . Genomics . 60 . 2 . 226–33 . Nov 1999 . 10486214 . 10.1006/geno.1999.5912 .
2. Salmikangas P, Mykkanen OM, Gronholm M, Heiska L, Kere J, Carpen O . Myotilin, a novel sarcomeric protein with two Ig-like domains, is encoded by a candidate gene for limb-girdle muscular dystrophy . Hum Mol Genet . 8 . 7 . 1329–36 . Aug 1999 . 10369880 . 10.1093/hmg/8.7.1329 . 16176213 . free .
3. Web site: Entrez Gene: MYOT myotilin.
4. Web site: Myotilin protein information . Cardiac Organellar Protein Atlas Knowledgebase (COPaKB) . 2015-03-23 . 2015-09-24 . https://web.archive.org/web/20150924025611/http://www.heartproteome.org/copa/ProteinInfo.aspx?QType=Protein%20ID&QValue=Q9JIF9 . dead .
5. 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 . Jul 1999 . 10369880 . 10.1093/hmg/8.7.1329 . 1329–36. 16176213 . free .
6. Shalaby S, Mitsuhashi H, Matsuda C, Minami N, Noguchi S, Nonaka I, Nishino I, Hayashi YK . Defective myotilin homodimerization caused by a novel mutation in MYOT exon 9 in the first Japanese limb girdle muscular dystrophy 1A patient . Journal of Neuropathology and Experimental Neurology . 68 . 6 . Jun 2009 . 19458539 . 10.1097/NEN.0b013e3181a7f703 . 701–7. free .
7. Selcen D . Myofibrillar myopathies . Neuromuscular Disorders . 21 . 3 . Mar 2011 . 21256014 . 10.1016/j.nmd.2010.12.007 . 161–71 . 3052736.
8. Salmikangas P, van der Ven PF, Lalowski M, Taivainen A, Zhao F, Suila H, Schröder R, Lappalainen P, Fürst DO, Carpén O . Myotilin, the limb-girdle muscular dystrophy 1A (LGMD1A) protein, cross-links actin filaments and controls sarcomere assembly . Human Molecular Genetics . 12 . 2 . Jan 2003 . 12499399 . 10.1093/hmg/ddg020 . 189–203. free .
9. van der Ven PF, Wiesner S, Salmikangas P, Auerbach D, Himmel M, Kempa S, Hayess K, Pacholsky D, Taivainen A, Schröder R, Carpén O, Fürst DO . Indications for a novel muscular dystrophy pathway. gamma-filamin, the muscle-specific filamin isoform, interacts with myotilin . The Journal of Cell Biology . 151 . 2 . Oct 2000 . 11038172 . 10.1083/jcb.151.2.235 . 2192634 . 235–248.
10. Gontier Y, Taivainen A, Fontao L, Sonnenberg A, van der Flier A, Carpen O, Faulkner G, Borradori L . The Z-disc proteins myotilin and FATZ-1 interact with each other and are connected to the sarcolemma via muscle-specific filamins . Journal of Cell Science . 118 . Pt 16 . Aug 2005 . 16076904 . 10.1242/jcs.02484 . 3739–49. free .
11. von Nandelstadh P, Ismail M, Gardin C, Suila H, Zara I, Belgrano A, Valle G, Carpen O, Faulkner G . A class III PDZ binding motif in the myotilin and FATZ families binds enigma family proteins: a common link for Z-disc myopathies . Molecular and Cellular Biology . 29 . 3 . Feb 2009 . 19047374 . 10.1128/MCB.01454-08 . 822–34 . 2630697.
12. Moza M et al . 2007 . Targeted deletion of the muscular dystrophy gene myotilin does not perturb muscle structure or function in mice . Mol Cell Biol . 27 . 1. 244–252 . 10.1128/mcb.00561-06. 17074808 . 1800670.
13. Garvey SM et al . 2006 . Transgenic mice expressing the myotilin T57I mutation unite the pathology associated with LGMD1A and MFM . Hum Mol Genet . 15 . 15. 2348–62 . 10.1093/hmg/ddl160 . 16801328. free .
14. von Nandelstadh P, Grönholm M, Moza M, Lamberg A, Savilahti H, Carpén O . Actin-organising properties of the muscular dystrophy protein myotilin . Experimental Cell Research . 310 . 1 . Oct 2005 . 16122733 . 10.1016/j.yexcr.2005.06.027 . 131–9.
15. von Nandelstadh P, Soliymani R, Baumann M, Carpen O . Analysis of myotilin turnover provides mechanistic insight into the role of myotilinopathy-causing mutations . The Biochemical Journal . 436 . 1 . May 2011 . 21361873 . 10.1042/BJ20101672 . 113–21.
16. Wang J, Dube DK, Mittal B, Sanger JM, Sanger JW . Myotilin dynamics in cardiac and skeletal muscle cells . Cytoskeleton . 68 . 12 . Dec 2011 . 22021208 . 10.1002/cm.20542 . 661–70 . 3240742.