Obscurin is aprotein that in humans is encoded by theOBSCNgene.[5][6][7] Obscurin belongs to the family of giantsarcomeric signaling proteins that includestitin andnebulin. Obscurin is expressed incardiac andskeletal muscle, and plays a role in the organization ofmyofibrils duringsarcomere assembly. A mutation in theOBSCN gene has been associated withhypertrophic cardiomyopathy and altered obscurin protein properties have been associated with other muscle diseases.
Obscurin belongs to the family of giantsarcomeric signaling proteins that includestitin andnebulin, and may have a role in the organization ofmyofibrils during assembly and may mediate interactions between thesarcoplasmic reticulum andmyofibrils. Obscurin is the majorcytoplasmicligand forsmall ankyrin 1 (sANK1), asarcoplasmic reticular protein, and the scaffolding function of obscurin appears to prevent degradation ofsANK1.[17] These data indicate that obscurin serves as a signaling link between thesarcomeric andsarcoplasmic reticular domains,[18][19] Obscurin plays a role in the formation of newsarcomeres duringmyofibril 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 ofmyosin filaments intosarcomeres and in the assembly ofA-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 withdilated cardiomyopathy.[25] An obscurin mutationArg4344Gln was identified in patients withhypertrophic cardiomyopathy, which disrupted binding of obscurin to the Z9-Z10 domains oftitin.[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 encodingtitin in patients withlimb-girdle muscular dystrophy 2J or Salih myopathy decrease the ability oftitin to bind obscurin, suggesting that this may be causative in disease manifestation.[30]
Obscurin has been shown tointeract withTitin,[5][31] specifically, with the Novex-3 ofTitin, a 6.5 kbexon located upstream of thecardiac-specific N2Bexon.[32] The C-terminal region of Obscurin interacts with the cytoplasmic domain ofsmall ankyrin 1[33][34] and with the exon 43' region ofankyrin B.[35] The Ig3 of obscurin bindsmyomesin at the linker between My4 and My5.[30]
^Russell MW, Raeker MO, Korytkowski KA, Sonneman KJ (Jan 2002). "Identification, tissue expression and chromosomal localization of human Obscurin-MLCK, a member of the titin and Dbl families of myosin light chain kinases".Gene.282 (1–2):237–46.doi:10.1016/S0378-1119(01)00795-8.PMID11814696.
^Fukuzawa A, Idowu S, Gautel M (2005). "Complete human gene structure of obscurin: implications for isoform generation by differential splicing".Journal of Muscle Research and Cell Motility.26 (6–8):427–34.doi:10.1007/s10974-005-9025-6.PMID16625316.S2CID20522555.
^Borisov AB, Raeker MO, Kontrogianni-Konstantopoulos A, Yang K, Kurnit DM, Bloch RJ, Russell MW (Oct 2003). "Rapid response of cardiac obscurin gene cluster to aortic stenosis: differential activation of Rho-GEF and MLCK and involvement in hypertrophic growth".Biochemical and Biophysical Research Communications.310 (3):910–8.doi:10.1016/j.bbrc.2003.09.035.PMID14550291.
^Arimura T, Matsumoto Y, Okazaki O, Hayashi T, Takahashi M, Inagaki N, et al. (October 2007). "Structural analysis of obscurin gene in hypertrophic cardiomyopathy".Biochemical and Biophysical Research Communications.362 (2):281–7.doi:10.1016/j.bbrc.2007.07.183.PMID17716621.
Kontrogianni-Konstantopoulos A, Catino DH, Strong JC, Randall WR, Bloch RJ (Jul 2004). "Obscurin regulates the organization of myosin into A bands".American Journal of Physiology. Cell Physiology.287 (1): C209-17.doi:10.1152/ajpcell.00497.2003.PMID15013951.
Brandenberger R, Wei H, Zhang S, Lei S, Murage J, Fisk GJ, Li Y, Xu C, Fang R, Guegler K, Rao MS, Mandalam R, Lebkowski J, Stanton LW (Jun 2004). "Transcriptome characterization elucidates signaling networks that control human ES cell growth and differentiation".Nature Biotechnology.22 (6):707–16.doi:10.1038/nbt971.PMID15146197.S2CID27764390.
Fukuzawa A, Idowu S, Gautel M (2007). "Complete human gene structure of obscurin: implications for isoform generation by differential splicing".Journal of Muscle Research and Cell Motility.26 (6–8):427–34.doi:10.1007/s10974-005-9025-6.PMID16625316.S2CID20522555.
Arimura T, Matsumoto Y, Okazaki O, Hayashi T, Takahashi M, Inagaki N, Hinohara K, Ashizawa N, Yano K, Kimura A (Oct 2007). "Structural analysis of obscurin gene in hypertrophic cardiomyopathy".Biochemical and Biophysical Research Communications.362 (2):281–7.doi:10.1016/j.bbrc.2007.07.183.PMID17716621.
