Obscurin

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

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

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

Clinical Significance
Obscurin has been shown to exhibit a disease-related isoform switch in patients with is_associated_with::dilated cardiomyopathy. An obscurin mutation Arg344Gln was identified in patients with is_associated_with::hypertrophic cardiomyopathy, which disrupted binding of obscurin to the Z9-Z10 domains of is_associated_with::titin. Mutations found the gene encoding titin in patients with is_associated_with::limb-girdle muscular dystrophy 2J or Salih myopathy decrease the ability of is_associated_with::titin to bind obscurin, suggesting that this may be causative in disease manifestation.

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