Group:MUZIC:Myotilin

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Contents

Introduction

Myotilin is a 498-amino-acid cytoskeletal protein with a 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 N-terminus, followed by two C-terminal half immunoglobulin (Ig)-like domains and a short C-terminal tail containing PDZ-binding motif (PBM).

Sequence annotation

Two alternately-spliced isoforms of human myotilin are currently known (UNIPROT Myotilin). Isoform-1 with 498 amino-acid sequence is the canonical form, while the second isoform lacks the first 184 amino-acid sequence.

Domain organisation in myotilin. Alternately spliced isoform-2 lacks the first 184 amino-acid residues










Structure

Molecular structures of individual myotilin immunoglobulin(Ig)-like domains have recently been solved. The first domain (Ig-1) exhibits an I-type Ig-fold [3], while the second domain (Ig-2) is of typical C2-type Ig-domain fold [4].

Solution NMR structure of the first Ig-domain of human myotilin (PDB ID: 2KDG [1]

Drag the structure with the mouse to rotate

Solution NMR structure of the second Ig-like (C2-type) domain of human myotilin (PDB ID:2KKQ [1]

Drag the structure with the mouse to rotate

Function and Interactions

Myotilin participates in a network of multi-protein interactions within the sarcomere, mainly via its Ig-domains, and both N- and C-termini. All myotilin binding partners are components of the Z-disc including actin (binds via its Ig-domains)[5]; α-actinin-2 (binds via a 17-amino acid region on its N-terminal half which shares high degree of homology with palladin α-actinin-2 binding region[6] [1]; filamin C (binds via the Ig-domains) [7]; FATZ-1 (via the Ig-domains)[8] and ZASP (binds via its C-terminal class III PDZ-binding motif)[9]. Myotilin forms homodimer and efficiently cross-links actin filaments[1], suggesting a contributory function in maintenance of contractile straited muscle. The muscle quality control proteins localised to the Z-discs (MuRF3 and MuRF1)[10] have also been shown to interact with myotilin. The appearance of myotilin with α-actinin-2 in Z-bodies of premyofibrils (at the very early stage of myofibre development) suggests essential role for myotilin in muscle formation [11] [12]. Similarly, upregulation of myotilin after exercise-induced alteration of myofibril and/or during myofibrillar remodelling (insertion of new sarcomeres into pre-exisitng myofibrils), suggests a role for myotilin essential in muscle repair [13]. Muscle disorders such as limb-girdle muscular dystrophy type 1A (LGMD1A) and myofibrillar myopathy (MFM) often resulting from several point mutations in myotilin, have further linked the protein to stabilisation role in myofibrils [14].

Pathology

Muscle disorders resulting from aberration(s) in myotilin gene are described as myotilinopathies [15], [16]. The disorders typically manifest as progressive proximal weakness of the extremities, pseudo-hypertropthy [17] and atrophy, but may also include cardiomyopathy and peripheral neuropathy. Ultrastructural changes include Z-disk alterations and accumulation of dense filamentous myotilin. Single missense mutations, mostly in the N-terminal serine-rich part of the protein, cause the onset of most disorders [18] [19]

References

  1. ↑ 1.0 1.1 1.2 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. ↑ Otey CA, Dixon R, Stack C, Goicoechea SM. Cytoplasmic Ig-domain proteins: cytoskeletal regulators with a role in human disease. Cell Motil Cytoskeleton. 2009 Aug;66(8):618-34. PMID:19466753 doi:10.1002/cm.20385
  5. ↑ 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
  6. ↑ Beck MR, Otey CA, Campbell SL. Structural characterization of the interactions between palladin and alpha-actinin. J Mol Biol. 2011 Oct 28;413(3):712-25. doi: 10.1016/j.jmb.2011.08.059. Epub 2011 , Sep 8. PMID:21925511 doi:10.1016/j.jmb.2011.08.059
  7. ↑ 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
  8. ↑ 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
  9. ↑ 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
  10. ↑ 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
  11. ↑ 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
  12. ↑ 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
  13. ↑ Carlsson L, Yu JG, Moza M, Carpen O, Thornell LE. Myotilin: a prominent marker of myofibrillar remodelling. Neuromuscul Disord. 2007 Jan;17(1):61-8. Epub 2006 Oct 23. PMID:17056257 doi:10.1016/j.nmd.2006.09.007
  14. ↑ 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
  15. ↑ Olive M, Goldfarb LG, Shatunov A, Fischer D, Ferrer I. Myotilinopathy: refining the clinical and myopathological phenotype. Brain. 2005 Oct;128(Pt 10):2315-26. Epub 2005 Jun 9. PMID:15947064 doi:10.1093/brain/awh576
  16. ↑ Penisson-Besnier I, Talvinen K, Dumez C, Vihola A, Dubas F, Fardeau M, Hackman P, Carpen O, Udd B. Myotilinopathy in a family with late onset myopathy. Neuromuscul Disord. 2006 Jul;16(7):427-31. Epub 2006 Jun 21. PMID:16793270 doi:10.1016/j.nmd.2006.04.009
  17. ↑ Gamez J, Armstrong J, Shatunov A, Selva-O'Callaghan A, Dominguez-Oronoz R, Ortega A, Goldfarb L, Ferrer I, Olive M. Generalized muscle pseudo-hypertrophy and stiffness associated with the myotilin Ser55Phe mutation: a novel myotilinopathy phenotype? J Neurol Sci. 2009 Feb 15;277(1-2):167-71. doi: 10.1016/j.jns.2008.10.019. Epub, 2008 Nov 22. PMID:19027924 doi:10.1016/j.jns.2008.10.019
  18. ↑ 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
  19. ↑ Selcen D, Carpen O. The Z-disk diseases. Adv Exp Med Biol. 2008;642:116-30. PMID:19181098

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