Obscurin is a protein that in humans is encoded by the OBSCNgene.[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.
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 sarcomericM-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
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.[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
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
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]
↑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.
↑ 11.011.1Carlsson L, Yu JG, Thornell LE (Jul 2008). "New aspects of obscurin in human striated muscles". Histochemistry and Cell Biology. 130 (1): 91–103. doi:10.1007/s00418-008-0413-z. PMID18350308.
↑Borisov AB, Kontrogianni-Konstantopoulos A, Bloch RJ, Westfall MV, Russell MW (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. 52 (9): 1117–27. doi:10.1369/jhc.3A6183.2004. PMID15314079.
↑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.
↑Borisov AB, Sutter SB, Kontrogianni-Konstantopoulos A, Bloch RJ, Westfall MV, Russell MW (Mar 2006). "Essential role of obscurin in cardiac myofibrillogenesis and hypertrophic response: evidence from small interfering RNA-mediated gene silencing". Histochemistry and Cell Biology. 125 (3): 227–38. doi:10.1007/s00418-005-0069-x. PMID16205939.
↑Makarenko I, Opitz CA, Leake MC, Neagoe C, Kulke M, Gwathmey JK, del Monte F, Hajjar RJ, Linke WA (Oct 2004). "Passive stiffness changes caused by upregulation of compliant titin isoforms in human dilated cardiomyopathy hearts". Circulation Research. 95 (7): 708–16. doi:10.1161/01.RES.0000143901.37063.2f. PMID15345656.
↑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.
↑ 23.023.1Fukuzawa A, Lange S, Holt M, Vihola A, Carmignac V, Ferreiro A, Udd B, Gautel M (Jun 2008). "Interactions with titin and myomesin target obscurin and obscurin-like 1 to the M-band: implications for hereditary myopathies". Journal of Cell Science. 121 (Pt 11): 1841–51. doi:10.1242/jcs.028019. PMID18477606.
↑Pernigo S, Fukuzawa A, Pandini A, Holt M, Kleinjung J, Gautel M, Steiner RA (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. 427 (4): 718–36. doi:10.1016/j.jmb.2014.11.019. PMID25490259.
↑Bang ML, Centner T, Fornoff F, Geach AJ, Gotthardt M, McNabb M, Witt CC, Labeit D, Gregorio CC, Granzier H, Labeit S (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. 89 (11): 1065–72. doi:10.1161/hh2301.100981. PMID11717165.
Nagase T, Kikuno R, Nakayama M, Hirosawa M, Ohara O (Aug 2000). "Prediction of the coding sequences of unidentified human genes. XVIII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro". DNA Research. 7 (4): 273–81. doi:10.1093/dnares/7.4.271. PMID10997877.
Bang ML, Centner T, Fornoff F, Geach AJ, Gotthardt M, McNabb M, Witt CC, Labeit D, Gregorio CC, Granzier H, Labeit S (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. 89 (11): 1065–72. doi:10.1161/hh2301.100981. PMID11717165.
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.
Borisov AB, Sutter SB, Kontrogianni-Konstantopoulos A, Bloch RJ, Westfall MV, Russell MW (Mar 2006). "Essential role of obscurin in cardiac myofibrillogenesis and hypertrophic response: evidence from small interfering RNA-mediated gene silencing". Histochemistry and Cell Biology. 125 (3): 227–38. doi:10.1007/s00418-005-0069-x. PMID16205939.
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.
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.
Borzok MA, Catino DH, Nicholson JD, Kontrogianni-Konstantopoulos A, Bloch RJ (Nov 2007). "Mapping the binding site on small ankyrin 1 for obscurin". The Journal of Biological Chemistry. 282 (44): 32384–96. doi:10.1074/jbc.M704089200. PMID17720975.
