Biology:MYOT

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Short description: Mammalian protein found in Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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,[10] 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]

References

  1. ↑ "TTID: A novel gene at 5q31 encoding a protein with titin-like features". Genomics 60 (2): 226–33. Nov 1999. doi:10.1006/geno.1999.5912. PMID 10486214. 
  2. ↑ "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. doi:10.1093/hmg/8.7.1329. PMID 10369880. 
  3. ↑ "Entrez Gene: MYOT myotilin". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=9499. 
  4. ↑ "Myotilin protein information". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB). http://www.heartproteome.org/copa/ProteinInfo.aspx?QType=Protein%20ID&QValue=Q9JIF9. 
  5. ↑ "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. Jul 1999. doi:10.1093/hmg/8.7.1329. PMID 10369880. 
  6. ↑ "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. Jun 2009. doi:10.1097/NEN.0b013e3181a7f703. PMID 19458539. 
  7. ↑ 7.0 7.1 "Myofibrillar myopathies". Neuromuscular Disorders 21 (3): 161–71. Mar 2011. doi:10.1016/j.nmd.2010.12.007. PMID 21256014. 
  8. ↑ "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. doi:10.1093/hmg/ddg020. PMID 12499399. 
  9. ↑ "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. Oct 2000. doi:10.1083/jcb.151.2.235. PMID 11038172. 
  10. ↑ 10.0 10.1 "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. doi:10.1242/jcs.02484. PMID 16076904. 
  11. ↑ "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. Feb 2009. doi:10.1128/MCB.01454-08. PMID 19047374. 
  12. ↑ "Targeted deletion of the muscular dystrophy gene myotilin does not perturb muscle structure or function in mice". Mol Cell Biol 27 (1): 244–252. 2007. doi:10.1128/mcb.00561-06. PMID 17074808. 
  13. ↑ "Transgenic mice expressing the myotilin T57I mutation unite the pathology associated with LGMD1A and MFM". Hum Mol Genet 15 (15): 2348–62. 2006. doi:10.1093/hmg/ddl160. PMID 16801328. 
  14. ↑ "Actin-organising properties of the muscular dystrophy protein myotilin". Experimental Cell Research 310 (1): 131–9. Oct 2005. doi:10.1016/j.yexcr.2005.06.027. PMID 16122733. 
  15. ↑ "Analysis of myotilin turnover provides mechanistic insight into the role of myotilinopathy-causing mutations". The Biochemical Journal 436 (1): 113–21. May 2011. doi:10.1042/BJ20101672. PMID 21361873. 
  16. ↑ "Myotilin dynamics in cardiac and skeletal muscle cells". Cytoskeleton 68 (12): 661–70. Dec 2011. doi:10.1002/cm.20542. PMID 22021208. 

Further reading

External links



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