Obscurin is a
protein that in humans is encoded by the OBSCNgene.[5][6][7] 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
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 calcium/calmodulin-binding domain, 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]
Function
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
cytoplasmicligand 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]
Clinical significance
Obscurin has been shown to exhibit a disease-related isoform switch in patients with
dilated cardiomyopathy.[25] An obscurin mutation
Arg4344
Gln 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]
Interactions
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]
^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.