Obscurin

Human obscurin may exist as multiple splice variants of approximately 720 kDa,^{[8][9][10][11][12]} however the full-length nature of only one has been described to date.^[13] Obscurin is expressed in cardiac and skeletal muscle. The obscurin gene spans more than 150 kb, contains over 80 exons.^[14] The encoded protein contains 68 Ig domains, 2 fibronectin domains, 1 IQ calmodulin-binding motif, 1 RhoGEF domain with an associated PH domain, and 2 serine-threonine kinase domains.^[13] The dominant location of obscurin in mature myofibrils is at the sarcomeric M-band.^[13][15] Titin, obscurin, obscurin-like-1 and myomesin form a ternary complex at sarcomeric M-bands that is critical for sarcomere mechanics.^[16]

Obscurin belongs to the family of giant sarcomeric signaling proteins that includes titin and nebulin, and may have a role in the organization of myofibrils during assembly and may mediate interactions between the sarcoplasmic reticulum and myofibrils. Obscurin is the major cytoplasmic ligand for small ankyrin 1 (sANK1), a sarcoplasmic reticular protein, and the scaffolding function of obscurin appears to prevent degradation of sANK1.^[17] These data indicate that obscurin serves as a signaling link between the sarcomeric and sarcoplasmic reticular domains,^[18][19] Obscurin plays a role in the formation of new sarcomeres during myofibril assembly.^[20] specifically, at the sarcomeric periphery where sites of initiation and progression of myofibrilogenesis lie.^[21][22] Obscurin appears to be necessary for the proper incorporation of myosin filaments into sarcomeres and in the assembly of A-bands.^[15][23] Moreover, the kinase domains of obscurin are enzymatically active and appear to be involved in the regulation of cell adhesion.^[24]

Obscurin has been shown to exhibit a disease-related isoform switch in patients with dilated cardiomyopathy.^[25] An obscurin mutation Arg4344Gln was identified in patients with hypertrophic cardiomyopathy, which disrupted binding of obscurin to the Z9-Z10 domains of titin.^[26] A later study, however, was not able to reproduce this effect.^[27] Due to lack of mechanistic evidence and the high prevalence among African Americans, the Arg4344Gln variant is currently not considered to be pathogenic.^[28][29] Mutations found the gene encoding titin in patients with limb-girdle muscular dystrophy 2J or Salih myopathy decrease the ability of titin to bind obscurin, suggesting that this may be causative in disease manifestation.^[30]

Obscurin has been shown to interact with Titin,^[5][31] specifically, with the Novex-3 of Titin, a 6.5 kb exon located upstream of the cardiac-specific N2B exon.^[32] The C-terminal region of Obscurin interacts with the cytoplasmic domain of small ankyrin 1^[33][34] and with the exon 43' region of ankyrin B.^[35] The Ig3 of obscurin binds myomesin at the linker between My4 and My5.^[30]