MYOT

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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] 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[edit]

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 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. 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,[10] FATZ-2 [11] and ZASP.[12]

Function[edit]

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.[13] On the other hand, transgenic mice with mutated myotilin develop muscle dystrophy.[14]

Clinical significance[edit]

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,[15] albeit with a slower rate of degradation.[16] 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.[17]

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. ^ "Entrez Gene: MYOT myotilin". 
  4. ^ "Myotilin protein information". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB). 
  5. ^ 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). PMID 10369880. 
  6. ^ Shalaby S, Mitsuhashi H, Matsuda C, Minami N, Noguchi S, Nonaka I et al. (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). doi:10.1097/NEN.0b013e3181a7f703. PMID 19458539. 
  7. ^ a b Selcen D (Mar 2011). "Myofibrillar myopathies". Neuromuscular Disorders 21 (3). doi:10.1016/j.nmd.2010.12.007. PMID 21256014. 
  8. ^ Salmikangas P, van der Ven PF, Lalowski M, Taivainen A, Zhao F, Suila H et al. (Jan 2003). "Myotilin, the limb-girdle muscular dystrophy 1A (LGMD1A) protein, cross-links actin filaments and controls sarcomere assembly". Human Molecular Genetics 12 (2). PMID 12499399. 
  9. ^ van der Ven PF, Wiesner S, Salmikangas P, Auerbach D, Himmel M, Kempa S et al. (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). PMID 11038172. 
  10. ^ Gontier Y, Taivainen A, Fontao L, Sonnenberg A, van der Flier A, Carpen O et al. (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). doi:10.1242/jcs.02484. PMID 16076904. 
  11. ^ Gontier Y, Taivainen A, Fontao L, Sonnenberg A, van der Flier A, Carpen O et al. (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). doi:10.1242/jcs.02484. PMID 16076904. 
  12. ^ von Nandelstadh P, Ismail M, Gardin C, Suila H, Zara I, Belgrano A et al. (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). doi:10.1128/MCB.01454-08. PMID 19047374. 
  13. ^ 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
  14. ^ 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
  15. ^ 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). doi:10.1016/j.yexcr.2005.06.027. PMID 16122733. 
  16. ^ 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). doi:10.1042/BJ20101672. PMID 21361873. 
  17. ^ Wang J, Dube DK, Mittal B, Sanger JM, Sanger JW (Dec 2011). "Myotilin dynamics in cardiac and skeletal muscle cells". Cytoskeleton 68 (12). doi:10.1002/cm.20542. PMID 22021208. 

Further reading[edit]

External links[edit]