Myotilin

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Myotilin
Protein MYOT PDB 2KDG.png
Rendering based on PDB 2KDG.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols MYOT ; LGMD1; LGMD1A; MFM3; TTID; TTOD
External IDs OMIM604103 MGI1889800 HomoloGene4942 GeneCards: MYOT Gene
RNA expression pattern
PBB GE MYOT 219728 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 9499 58916
Ensembl ENSG00000120729 ENSMUSG00000024471
UniProt Q9UBF9 Q9JIF9
RefSeq (mRNA) NM_001135940 NM_001033621
RefSeq (protein) NP_001129412 NP_001028793
Location (UCSC) Chr 5:
137.2 – 137.22 Mb
Chr 18:
44.33 – 44.36 Mb
PubMed search [1] [2]

Myotilin is a protein that in humans is encoded by the MYOT gene.[1][2][3]

Striated muscle sarcomeres are highly organized structures composed of actin (thin) and myosin (thick) filaments that slide past each other during contraction. The integrity of sarcomeres is controlled by a set of structural proteins, among which are titin (TTN; MIM 188840), a giant molecule that contains several immunoglobulin (Ig)-like domains and associates with thin and thick filaments, and alpha-actinin (ACTN1; MIM 102575), an actin cross-linking protein. Mutations in several sarcomeric and sarcolemmal proteins have been shown to result in muscular dystrophy and cardiomyopathy.[supplied by OMIM][3]
Myotilin (myofibrillar titin-like protein) also known as TTID (TiTin Immunoglobulin Domain) is a skeletal muscle protein that is found within the Z-disc of sarcomeres. It is mutated in various forms of muscular dystrophy:

- Limb-Girdle Muscular Dystrophy type 1A (LGMD1A)
- Myofibrillar Myopathy (MFM)
- Spheroid Body Myopathy
- Distal Myopathy

Myotilin was originally identified as a novel alpha-actinin binding partner with two Ig-like domains, that localised to the Z-disc.[4] The C2-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. 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. 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,[5] Filamin C,[6] FATZ-1[7] and ZASP.[8] 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 in this conditions appear more tightly packed than those induced by alpha-actinin alone. It was demonstrated that myotilin stabilises 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 co-localises with alpha-actinin and Z-disc titin, showing the striated pattern typical of sarcomeric proteins. Targeted disruption of myotilin gene in mice does not cause significant alteration in muscle function.[9] On the other hand, transgenic mice with mutated myotilin develop muscle dystrophy.[10]

References[edit]

  1. ^ 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. 
  2. ^ 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. 
  3. ^ a b "Entrez Gene: MYOT myotilin". 
  4. ^ Salmikangas, P., et al., Myotilin, a novel sarcomeric protein with two Ig-like domains, is encoded by a candidate gene for limb-girdle muscular dystrophy. Hum Mol Genet, 1999. 8(7): p. 1329-36
  5. ^ Salmikangas, P., et al., Myotilin, the limb-girdle muscular dystrophy 1A (LGMD1A) protein, cross-links actin filaments and controls sarcomere assembly. Hum Mol Genet, 2003. 12(2): p. 189-203
  6. ^ van der Ven, P.F., et al., Indications for a novel muscular dystrophy pathway. gamma-filamin, the muscle-specific filamin isoform, interacts with myotilin. J Cell Biol, 2000. 151(2): p. 235-48
  7. ^ Gontier, Y., et al., The Z-disc proteins myotilin and FATZ-1 interact with each other and are connected to the sarcolemma via muscle-specific filamins. J Cell Sci, 2005. 118(Pt 16): p. 3739-49.
  8. ^ von Nandelstadh, P., et al., A class III PDZ binding motif in myotilin and FATZ families binds Enigma family proteins – a common link for Zdisc myopathies. Mol Cell Biol, 2009.
  9. ^ Moza M, et al. Targeted deletion of the muscular dystrophy gene myotilin does not perturb muscle structure or function in mice. Mol Cell Biol. 2007, 27(1):244-252
  10. ^ Garvey, S.M., et al., Transgenic mice expressing the myotilin T57I mutation unite the pathology associated with LGMD1A and MFM. Hum Mol Genet, 2006. 15(15): p. 2348-62

External links[edit]

Further reading[edit]