Group:MUZIC:Myotilin

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Contents

Introduction

Myotilin is a cytoskeletal protein with the size of 57 kDa, localized in sarcomeric Z-discs of both skeletal and cardiac muscle [1]. It consists of a unique serine-rich amino-terminus, two Ig-domains and a short carboxy-terminus with a PDZ-binding motif (UNIPROT Myotilin). Myotilin belongs to a small group of scaffolding proteins, together with palladin and myopapalladin, which regulate actin organisation [2] but was also found to interact with several other sarcomeric proteins like actin, α-actinin, filamin C [3] [4] and FATZ-1/FATZ-2 [5]. Muscle disorders such as limb-girdle muscular dystrophy type 1A and myofibrillar myopathy (MFM) have been linked to point mutations in myotilin [6].


Pathology

The disorders typically manifest as proximal weakness of the extremities but may also include cardiomyopathy and peripheral neuropathy. Ultrastructural changes include Z-disk alterations and accumulation of dense filamentous myotilin. Single missense mutation, mostly in the N-terminal serine-rich part of the protein, causes the onset of both disorders. Thus, mutation has a dominant negative effect on functionality of myotilin [7] [8].


Interactions of Myotilin

Solution Structure of the 1st Ig domain of Myotilin

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Solution NMR Structure of the Ig-like C2-type 2 Domain of Human Myotilin

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References

  1. ↑ Salmikangas P, Mykkanen OM, Gronholm M, Heiska L, Kere J, Carpen O. 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 Jul;8(7):1329-36. PMID:10369880
  2. ↑ Otey CA, Rachlin A, Moza M, Arneman D, Carpen O. The palladin/myotilin/myopalladin family of actin-associated scaffolds. Int Rev Cytol. 2005;246:31-58. PMID:16164966 doi:10.1016/S0074-7696(05)46002-7
  3. ↑ Heikkinen O, Permi P, Koskela H, Carpen O, Ylanne J, Kilpelainen I. Solution structure of the first immunoglobulin domain of human myotilin. J Biomol NMR. 2009 Jun;44(2):107-12. Epub 2009 May 6. PMID:19418025 doi:10.1007/s10858-009-9320-4
  4. ↑ van der Ven PF, Wiesner S, Salmikangas P, Auerbach D, Himmel M, Kempa S, Hayess K, Pacholsky D, Taivainen A, Schroder R, Carpen O, Furst DO. Indications for a novel muscular dystrophy pathway. gamma-filamin, the muscle-specific filamin isoform, interacts with myotilin. J Cell Biol. 2000 Oct 16;151(2):235-48. PMID:11038172
  5. ↑ Gontier Y, Taivainen A, Fontao L, Sonnenberg A, van der Flier A, Carpen O, Faulkner G, Borradori L. 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 Aug 15;118(Pt 16):3739-49. Epub 2005 Aug 2. PMID:16076904 doi:10.1242/jcs.02484
  6. ↑ Moza M, Mologni L, Trokovic R, Faulkner G, Partanen J, Carpen O. Targeted deletion of the muscular dystrophy gene myotilin does not perturb muscle structure or function in mice. Mol Cell Biol. 2007 Jan;27(1):244-52. Epub 2006 Oct 30. PMID:17074808 doi:10.1128/MCB.00561-06
  7. ↑ Hauser MA, Horrigan SK, Salmikangas P, Torian UM, Viles KD, Dancel R, Tim RW, Taivainen A, Bartoloni L, Gilchrist JM, Stajich JM, Gaskell PC, Gilbert JR, Vance JM, Pericak-Vance MA, Carpen O, Westbrook CA, Speer MC. Myotilin is mutated in limb girdle muscular dystrophy 1A. Hum Mol Genet. 2000 Sep 1;9(14):2141-7. PMID:10958653
  8. ↑ Selcen D, Carpen O. The Z-disk diseases. Adv Exp Med Biol. 2008;642:116-30. PMID:19181098

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