Obscurin

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 IQ calmodulin-binding motif, 1 RhoGEF domain with an associated PH domain, and 2 serine-threonine kinase domains. The dominant location of obscurin in mature myofibrils is at the sarcomeric M-band. Titin, obscurin, obscurin-like-1 and myomesin form a ternary complex at sarcomeric M-bands that is critical for sarcomere mechanics.

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 cytoplasmic 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 sarcomeres during 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 myosin filaments into 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 dilated cardiomyopathy. An obscurin mutation Arg4344Gln was identified in patients with hypertrophic cardiomyopathy, which disrupted binding of obscurin to the Z9-Z10 domains of titin. A later study, however, was not able to reproduce this effect. Due to lack of mechanistic evidence and the high prevalence among African Americans, the Arg4344Gln variant is currently not considered to be pathogenic. 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.

Interactions

Obscurin has been shown to interact with Titin, specifically, with the Novex-3 of Titin, a 6.5 kb exon located upstream of the cardiac-specific N2B 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.

References

References

1. (Jul 2001). "Obscurin, a giant sarcomeric Rho guanine nucleotide exchange factor protein involved in sarcomere assembly". The Journal of Cell Biology.
2. (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.
3. "Entrez Gene: OBSCN obscurin, cytoskeletal calmodulin and titin-interacting RhoGEF".
4. "Q5VST9".
5. "Q5VST9-6".
6. "Q5VST9-2".
7. "Q5VST9-3".
8. "Q5VST9-5".
9. (Jul 2001). "Obscurin, a giant sarcomeric Rho guanine nucleotide exchange factor protein involved in sarcomere assembly". The Journal of Cell Biology.
10. (2005). "Complete human gene structure of obscurin: implications for isoform generation by differential splicing". Journal of Muscle Research and Cell Motility.
11. (Jul 2008). "New aspects of obscurin in human striated muscles". Histochemistry and Cell Biology.
12. (Feb 2010). "Structural insight into M-band assembly and mechanics from the titin-obscurin-like-1 complex". Proceedings of the National Academy of Sciences of the United States of America.
13. (Jul 2012). "Obscurin and KCTD6 regulate cullin-dependent small ankyrin-1 (sAnk1.5) protein turnover". Molecular Biology of the Cell.
14. (Jan 2003). "Binding of an ankyrin-1 isoform to obscurin suggests a molecular link between the sarcoplasmic reticulum and myofibrils in striated muscles". The Journal of Cell Biology.
15. (Mar 2003). "Obscurin is a ligand for small ankyrin 1 in skeletal muscle". Molecular Biology of the Cell.
16. (Sep 2004). "Dynamics of obscurin localization during differentiation and remodeling of cardiac myocytes: obscurin as an integrator of myofibrillar structure". The Journal of Histochemistry and Cytochemistry.
17. (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.
18. (Apr 2008). "Early incorporation of obscurin into nascent sarcomeres: implication for myofibril assembly during cardiac myogenesis". Histochemistry and Cell Biology.
19. (Mar 2006). "Essential role of obscurin in cardiac myofibrillogenesis and hypertrophic response: evidence from small interfering RNA-mediated gene silencing". Histochemistry and Cell Biology.
20. (May 2013). "The kinase domains of obscurin interact with intercellular adhesion proteins". FASEB Journal.
21. (October 2004). "Passive stiffness changes caused by upregulation of compliant titin isoforms in human dilated cardiomyopathy hearts". Circulation Research.
22. (October 2007). "Structural analysis of obscurin gene in hypertrophic cardiomyopathy". Biochemical and Biophysical Research Communications.
23. (June 2021). "When is an obscurin variant pathogenic? The impact of Arg4344Gln and Arg4444Trp variants on protein-protein interactions and protein stability". Human Molecular Genetics.
24. (June 2021). "When is an obscurin variant pathogenic? The impact of Arg4344Gln and Arg4444Trp variants on protein-protein interactions and protein stability". Human Molecular Genetics.
25. (August 2016). "Genetic Misdiagnoses and the Potential for Health Disparities". The New England Journal of Medicine.
26. (June 2008). "Interactions with titin and myomesin target obscurin and obscurin-like 1 to the M-band: implications for hereditary myopathies". Journal of Cell Science.
27. (Feb 2015). "The crystal structure of the human titin:obscurin complex reveals a conserved yet specific muscle M-band zipper module". Journal of Molecular Biology.
28. (Nov 2001). "The complete gene sequence of titin, expression of an unusual approximately 700-kDa titin isoform, and its interaction with obscurin identify a novel Z-line to I-band linking system". Circulation Research.
29. (Mar 2003). "Obscurin is a ligand for small ankyrin 1 in skeletal muscle". Molecular Biology of the Cell.
30. (Apr 2011). "Electrostatic interactions mediate binding of obscurin to small ankyrin 1: biochemical and molecular modeling studies". Journal of Molecular Biology.
31. (Nov 2008). "Obscurin targets ankyrin-B and protein phosphatase 2A to the cardiac M-line". The Journal of Biological Chemistry.