Myotilin

Myotilin is a is_associated_with::protein that in humans is encoded by the MYOT is_associated_with::gene.

Myotilin (myofibrillar titin-like protein) also known as TTID (TiTin Immunoglobulin Domain) is a skeletal muscle protein that is found within the Z-disc of sarcomeres. It is mutated in various forms of muscular dystrophy:

- Limb-Girdle Muscular Dystrophy type 1A (LGMD1A)

- Myofibrillar Myopathy (MFM)

- Spheroid Body Myopathy

- Distal Myopathy

Myotilin was originally identified as a novel is_associated_with::alpha-actinin binding partner with two Ig-like domains, that localised to the Z-disc. The C2-type Ig-like domains reside at the C-terminal half, and are most homologous to Ig domains 2-3 of is_associated_with::palladin and Ig domains 4-5 of is_associated_with::myopalladin and more distantly related to Z-disc Ig domains 7 and 8 of is_associated_with::titin. 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. 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, Filamin C, FATZ-1 and ZASP. 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 in this conditions appear more tightly packed than those induced by alpha-actinin alone. It was demonstrated that myotilin stabilises 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 is_associated_with::titin in amorphous cytoplasmic precipitates. In mature sarcomeres, wild-type myotilin co-localises with alpha-actinin and Z-disc titin, showing the striated pattern typical of sarcomeric proteins. Targeted disruption of myotilin gene in mice does not cause significant alteration in muscle function. On the other hand, transgenic mice with mutated myotilin develop muscle dystrophy.