Myotilin is aprotein that in humans is encoded by theMYOTgene.[5][6][7] Myotilin (myofibrillar titin-like protein) also known as TTID (TiTin Immunoglobulin Domain) is a muscle protein that is found within theZ-disc ofsarcomeres.
Myotilin is a 55.3 kDa protein composed of 496 amino acids.[8] Myotilin was originally identified as a novelalpha-actinin binding partner with twoIg-like domains, that localized to theZ-disc.[9] The I-typeIg-like domains reside at the C-terminal half, and are most homologous toIg domains 2-3 ofpalladin andIg domains 4-5 ofmyopalladin and more distantly related toZ-discIg domains 7 and 8 oftitin. The C-terminal region hosts the binding sites for Z-band proteins, and 2Ig domains are the site of homodimerization for myotilin.[10] By contrast, the N-terminal part of myotilin is unique, consisting of aserine-rich region with no homology to known proteins. Several disease-associated mutations involveserine residues within theserine-rich domain.[11] Myotilin expression in human tissues is mainly restricted to striated muscles and nerves. In muscles, myotilin is predominantly found within theZ-discs. Myotilin forms homodimers and bindsalpha-actinin,actin,[12]Filamin C,[13]FATZ-1,[14]FATZ-2[14] andZASP.[15]
Myotilin is a structural protein that, along withtitin andalpha-actinin give structural integrity tosarcomeres atZ-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 andactin bundles formed under these conditions appear more tightly packed than those induced byalpha-actinin alone. It was demonstrated that myotilin stabilizesF-actin by slowing down the disassembly rate. Ectopic overexpression of truncated myotilin causes the disruption of nascent myofibrils and the co-accumulation of myotilin andtitin in amorphous cytoplasmic precipitates. In maturesarcomeres, wild-type myotilin colocalizes withalpha-actinin andZ-disctitin, showing the striated pattern typical ofsarcomeric proteins. Targeted disruption of the myotilin gene in mice does not cause significant alterations in muscle function.[16] On the other hand, transgenic mice with mutated myotilin develop muscle dystrophy.[17]
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.[11] 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, andSer95Ile) are normal,[18] albeit with a slower rate of degradation.[19] Surprisingly, YFP-fusion constructs of myotilin mutants (Ser55Phe,Ser55Ile,Thr57Ile,Ser60Cys,Ser60Phe,Ser95Ile,Arg405Lys) localized normally toZ-discs and exhibited normal dynamics in muscle cells.[20]
^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):131–9.doi:10.1016/j.yexcr.2005.06.027.PMID16122733.
^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):113–21.doi:10.1042/BJ20101672.PMID21361873.
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Battle MA, Maher VM, McCormick JJ (Jun 2003). "ST7 is a novel low-density lipoprotein receptor-related protein (LRP) with a cytoplasmic tail that interacts with proteins related to signal transduction pathways".Biochemistry.42 (24):7270–82.doi:10.1021/bi034081y.PMID12809483.
Witt SH, Granzier H, Witt CC, Labeit S (Jul 2005). "MURF-1 and MURF-2 target a specific subset of myofibrillar proteins redundantly: towards understanding MURF-dependent muscle ubiquitination".Journal of Molecular Biology.350 (4):713–22.doi:10.1016/j.jmb.2005.05.021.PMID15967462.
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):131–9.doi:10.1016/j.yexcr.2005.06.027.PMID16122733.
Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M (Oct 2005). "Towards a proteome-scale map of the human protein-protein interaction network".Nature.437 (7062):1173–8.Bibcode:2005Natur.437.1173R.doi:10.1038/nature04209.PMID16189514.S2CID4427026.
Foroud T, Pankratz N, Batchman AP, Pauciulo MW, Vidal R, Miravalle L, Goebel HH, Cushman LJ, Azzarelli B, Horak H, Farlow M, Nichols WC (Dec 2005). "A mutation in myotilin causes spheroid body myopathy".Neurology.65 (12):1936–40.doi:10.1212/01.wnl.0000188872.28149.9a.PMID16380616.S2CID9593230.
Garvey SM, Senderek J, Beckmann JS, Seboun E, Jackson CE, Hauser MA (May 2006). "Myotilin is not the causative gene for vocal cord and pharyngeal weakness with distal myopathy (VCPDM)".Annals of Human Genetics.70 (Pt 3):414–6.doi:10.1111/j.1529-8817.2005.00252.x.PMID16674563.S2CID26853063.
Pénisson-Besnier I, Talvinen K, Dumez C, Vihola A, Dubas F, Fardeau M, Hackman P, Carpen O, Udd B (Jul 2006). "Myotilinopathy in a family with late onset myopathy".Neuromuscular Disorders.16 (7):427–31.doi:10.1016/j.nmd.2006.04.009.PMID16793270.S2CID21589529.
