Group:MUZIC:Myotilin

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Contents

Introduction

Myotilin is a 498-amino-acid cytoskeletal protein with the size of 55 kDa, localized in sarcomeric Z-discs of both skeletal and cardiac muscle[1]. It belongs to a small group of scaffolding proteins, together with palladin and myopapalladin, which regulate actin organisation[2]. Myotilin consists of a unique serine-rich amino-terminus, followed by two c-terminal half immunoglobulin-like (Ig) domains and a short carboxy-terminus containing PDZ-binding motif (UNIPROT Myotilin). Major proteins of the sarcomeric Z-disk have been reported to interact with myotilin, inlcuding alpha-actinin-2, filamin C, ZASP, FATZ [3] [4] [5] as well as the Z-disk localized muscle quality control proteins - MuRFs (MuRF3 and MuRF1)[6]. The appearance of myotilin with alpha-actinin-2 and other proteins in Z-bodies of premyofibrils, at the very early stage of myofibre development, suggests essential role for the protein in muscle formation [7] [8]. Likewise, muscle disorders such as limb-girdle muscular dystrophy type 1A (LGMD1A) and myofibrillar myopathy (MFM) which results from several point mutations in myotilin have linked the protein to stabilization role in myofibrils [9].

Structures

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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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.[10] [11]

Interactions of Myotilin

All myotilin's binding partners are components of Z-disk and include actin,[12] α-actinin-2,[13] filamin C, FATZ[14] and ZASP[15]. Myotilin cross-links and efficiently bundles actin filaments.[16]

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. ↑ Lange S, Ehler E, Gautel M. From A to Z and back? Multicompartment proteins in the sarcomere. Trends Cell Biol. 2006 Jan;16(1):11-8. Epub 2005 Dec 6. PMID:16337382 doi:10.1016/j.tcb.2005.11.007
  7. ↑ Sanger JW, Wang J, Fan Y, White J, Sanger JM. Assembly and dynamics of myofibrils. J Biomed Biotechnol. 2010;2010:858606. doi: 10.1155/2010/858606. Epub 2010 Jun, 10. PMID:20625425 doi:10.1155/2010/858606
  8. ↑ Wang J, Dube DK, Mittal B, Sanger JM, Sanger JW. Myotilin dynamics in cardiac and skeletal muscle cells. Cytoskeleton (Hoboken). 2011 Dec;68(12):661-70. doi: 10.1002/cm.20542. Epub 2011 , Nov 8. PMID:22021208 doi:10.1002/cm.20542
  9. ↑ 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
  10. ↑ 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
  11. ↑ Selcen D, Carpen O. The Z-disk diseases. Adv Exp Med Biol. 2008;642:116-30. PMID:19181098
  12. ↑ von Nandelstadh P, Gronholm M, Moza M, Lamberg A, Savilahti H, Carpen O. Actin-organising properties of the muscular dystrophy protein myotilin. Exp Cell Res. 2005 Oct 15;310(1):131-9. PMID:16122733 doi:10.1016/j.yexcr.2005.06.027
  13. ↑ 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
  14. ↑ 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
  15. ↑ von Nandelstadh P, Ismail M, Gardin C, Suila H, Zara I, Belgrano A, Valle G, Carpen O, Faulkner G. A class III PDZ binding motif in the myotilin and FATZ families binds enigma family proteins: a common link for Z-disc myopathies. Mol Cell Biol. 2009 Feb;29(3):822-34. Epub 2008 Dec 1. PMID:19047374 doi:10.1128/MCB.01454-08
  16. ↑ Salmikangas P, van der Ven PF, Lalowski M, Taivainen A, Zhao F, Suila H, Schroder R, Lappalainen P, Furst DO, Carpen O. Myotilin, the limb-girdle muscular dystrophy 1A (LGMD1A) protein, cross-links actin filaments and controls sarcomere assembly. Hum Mol Genet. 2003 Jan 15;12(2):189-203. PMID:12499399

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