MYOT
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesMYOT, LGMD1, LGMD1A, MFM3, TTID, TTOD, myotilin
External IDsOMIM: 604103 MGI: 1889800 HomoloGene: 4942 GeneCards: MYOT
Orthologs
SpeciesHumanMouse
Entrez

9499

58916

Ensembl

ENSG00000120729

ENSMUSG00000024471

UniProt

Q9UBF9

Q9JIF9

RefSeq (mRNA)

NM_006790
NM_001135940
NM_001300911

NM_001033621

RefSeq (protein)

NP_001129412
NP_001287840
NP_006781

NP_001028793

Location (UCSC)Chr 5: 137.87 – 137.89 MbChr 18: 44.47 – 44.49 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Myotilin is a protein that in humans is encoded by the MYOT gene.[5][6][7] 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.[8] Myotilin was originally identified as a novel alpha-actinin binding partner with two Ig-like domains, that localized to the Z-disc.[9] 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.[10] 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.[11] 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,[12] Filamin C,[13] FATZ-1,[14] FATZ-2[14] and ZASP.[15]

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.[16] On the other hand, transgenic mice with mutated myotilin develop muscle dystrophy.[17]

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.[11] 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,[18] albeit with a slower rate of degradation.[19] 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.[20]

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000120729 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000024471 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Godley LA, Lai F, Liu J, Zhao N, Le Beau MM (Nov 1999). "TTID: A novel gene at 5q31 encoding a protein with titin-like features". Genomics. 60 (2): 226–33. doi:10.1006/geno.1999.5912. PMID 10486214.
  6. ↑ Salmikangas P, Mykkanen OM, Gronholm M, Heiska L, Kere J, Carpen O (Aug 1999). "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. doi:10.1093/hmg/8.7.1329. PMID 10369880. S2CID 16176213.
  7. ↑ "Entrez Gene: MYOT myotilin".
  8. ↑ "Myotilin protein information". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB).
  9. ↑ Salmikangas P, Mykkänen OM, Grönholm M, Heiska L, Kere J, Carpén O (Jul 1999). "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. doi:10.1093/hmg/8.7.1329. PMID 10369880. S2CID 16176213.
  10. ↑ Shalaby S, Mitsuhashi H, Matsuda C, Minami N, Noguchi S, Nonaka I, Nishino I, Hayashi YK (Jun 2009). "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): 701–7. doi:10.1097/NEN.0b013e3181a7f703. PMID 19458539.
  11. 1 2 Selcen D (Mar 2011). "Myofibrillar myopathies". Neuromuscular Disorders. 21 (3): 161–71. doi:10.1016/j.nmd.2010.12.007. PMC 3052736. PMID 21256014.
  12. ↑ Salmikangas P, van der Ven PF, Lalowski M, Taivainen A, Zhao F, Suila H, Schröder R, Lappalainen P, Fürst DO, Carpén O (Jan 2003). "Myotilin, the limb-girdle muscular dystrophy 1A (LGMD1A) protein, cross-links actin filaments and controls sarcomere assembly". Human Molecular Genetics. 12 (2): 189–203. doi:10.1093/hmg/ddg020. PMID 12499399.
  13. ↑ 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 (Oct 2000). "Indications for a novel muscular dystrophy pathway. gamma-filamin, the muscle-specific filamin isoform, interacts with myotilin". The Journal of Cell Biology. 151 (2): 235–248. doi:10.1083/jcb.151.2.235. PMC 2192634. PMID 11038172.
  14. 1 2 Gontier Y, Taivainen A, Fontao L, Sonnenberg A, van der Flier A, Carpen O, Faulkner G, Borradori L (Aug 2005). "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. doi:10.1242/jcs.02484. PMID 16076904.
  15. ↑ von Nandelstadh P, Ismail M, Gardin C, Suila H, Zara I, Belgrano A, Valle G, Carpen O, Faulkner G (Feb 2009). "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): 822–34. doi:10.1128/MCB.01454-08. PMC 2630697. PMID 19047374.
  16. ↑ 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. doi:10.1128/mcb.00561-06. PMC 1800670. PMID 17074808.
  17. ↑ 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. doi:10.1093/hmg/ddl160. PMID 16801328.
  18. ↑ von Nandelstadh P, Grönholm M, Moza M, Lamberg A, Savilahti H, Carpén O (Oct 2005). "Actin-organising properties of the muscular dystrophy protein myotilin". Experimental Cell Research. 310 (1): 131–9. doi:10.1016/j.yexcr.2005.06.027. PMID 16122733.
  19. ↑ von Nandelstadh P, Soliymani R, Baumann M, Carpen O (May 2011). "Analysis of myotilin turnover provides mechanistic insight into the role of myotilinopathy-causing mutations". The Biochemical Journal. 436 (1): 113–21. doi:10.1042/BJ20101672. PMID 21361873.
  20. ↑ Wang J, Dube DK, Mittal B, Sanger JM, Sanger JW (Dec 2011). "Myotilin dynamics in cardiac and skeletal muscle cells". Cytoskeleton. 68 (12): 661–70. doi:10.1002/cm.20542. PMC 3240742. PMID 22021208.

Further reading

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