Obscurin

Obscurin is a protein that in humans is encoded by the OBSCN gene.^[1][2][3] Obscurin belongs to the family of giant sarcomeric signaling proteins that includes titin and nebulin. Obscurin is expressed in cardiac and skeletal muscle, and plays a role in the organization of myofibrils during sarcomere assembly. A mutation in the OBSCN gene has been associated with hypertrophic cardiomyopathy and altered obscurin protein properties have been associated with other muscle diseases.

Structure[edit | edit source]

Human obscurin may exist as multiple splice variants of approximately 720 kDa,^{[4][5][6][7][8]} however the full-length nature of only one has been described to date.^[9] Obscurin is expressed in cardiac and skeletal muscle. The obscurin gene spans more than 150 kb, contains over 80 exons.^[10] The encoded protein contains 68 Ig domains, 2 fibronectin domains, 1 calcium/calmodulin-binding domain, 1 RhoGEF domain with an associated PH domain, and 2 serine-threonine kinase domains.^[9] The dominant location of obscurin in mature myofibrils is at the sarcomeric M-band.^[9][11] Titin, obscurin, obscurin-like-1 and myomesin form a ternary complex at sarcomeric M-bands that is critical for sarcomere mechanics.^[12]

Function[edit | edit source]

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.^[13] These data indicate that obscurin serves as a signaling link between the sarcomeric and sarcoplasmic reticular domains,^[14][15] Obscurin plays a role in the formation of new sarcomeres during myofibril assembly.^[16] specifically, at the sarcomeric periphery where sites of initiation and progression of myofibrilogenesis lie.^[17][18] Obscurin appears to be necessary for the proper incorporation of myosin filaments into sarcomeres and in the assembly of A-bands.^[11][19] Moreover, the kinase domains of obscurin are enzymatically active and appear to be involved in the regulation of cell adhesion.^[20]

Clinical Significance[edit | edit source]

Obscurin has been shown to exhibit a disease-related isoform switch in patients with dilated cardiomyopathy.^[21] An obscurin mutation Arg4344Gln was identified in patients with hypertrophic cardiomyopathy, which disrupted binding of obscurin to the Z9-Z10 domains of titin.^[22] 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.^[23]

Interactions[edit | edit source]

Obscurin has been shown to interact with Titin,^[1][24] specifically, with the Novex-3 of Titin, a 6.5 kb exon located upstream of the cardiac-specific N2B exon.^[25] The C-terminal region of Obscurin interacts with the cytoplasmic domain of small ankyrin 1^[26][27] and with the exon 43' region of ankyrin B.^[28] The Ig3 of obscurin binds myomesin at the linker between My4 and My5.^[23]

References[edit | edit source]

Further reading[edit | edit source]