MYOT

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.

MYOT
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesMYOT, LGMD1, LGMD1A, MFM3, TTID, TTOD, myotilin
External IDsOMIM: 604103 MGI: 1889800 HomoloGene: 4942 GeneCards: MYOT
Gene location (Human)
Chr.Chromosome 5 (human)[1]
Band5q31.2Start137,867,858 bp[1]
End137,887,851 bp[1]
RNA expression pattern
More reference expression data
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: 44.33 – 44.36 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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. GRCh38: Ensembl release 89: ENSG00000120729 - Ensembl, May 2017
  2. 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. 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. 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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