Obscurin Explained

Obscurin is a protein that in humans is encoded by the OBSCN gene.[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.

Structure

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 IQ calmodulin-binding motif, 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 sarcomeric M-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 cytoplasmic ligand 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] A later study, however, was not able to reproduce this effect.[23] Due to lack of mechanistic evidence and the high prevalence among African Americans, the Arg4344Gln variant is currently not considered to be pathogenic.[24] [25] 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.[26]

Interactions

Obscurin has been shown to interact with Titin,[1] [27] specifically, with the Novex-3 of Titin, a 6.5 kb exon located upstream of the cardiac-specific N2B exon.[28] The C-terminal region of Obscurin interacts with the cytoplasmic domain of small ankyrin 1[29] [30] and with the exon 43' region of ankyrin B.[31] The Ig3 of obscurin binds myomesin at the linker between My4 and My5.[26]

Further reading

Notes and References

  1. Young P, Ehler E, Gautel M . Obscurin, a giant sarcomeric Rho guanine nucleotide exchange factor protein involved in sarcomere assembly . The Journal of Cell Biology . 154 . 1 . 123–36 . Jul 2001 . 11448995 . 2196875 . 10.1083/jcb.200102110 .
  2. Russell MW, Raeker MO, Korytkowski KA, Sonneman KJ . 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 . Jan 2002 . 11814696 . 10.1016/S0378-1119(01)00795-8 .
  3. Web site: Entrez Gene: OBSCN obscurin, cytoskeletal calmodulin and titin-interacting RhoGEF.
  4. Web site: Q5VST9.
  5. Web site: Q5VST9-6 .
  6. Web site: Q5VST9-2 .
  7. Web site: Q5VST9-3 .
  8. Web site: Q5VST9-5 .
  9. Young P, Ehler E, Gautel M . Obscurin, a giant sarcomeric Rho guanine nucleotide exchange factor protein involved in sarcomere assembly . The Journal of Cell Biology . 154 . 1 . 123–36 . Jul 2001 . 11448995 . 10.1083/jcb.200102110 . 2196875.
  10. Fukuzawa A, Idowu S, Gautel M . 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 . 16625316 . 10.1007/s10974-005-9025-6 . 2005. 20522555 .
  11. Carlsson L, Yu JG, Thornell LE . New aspects of obscurin in human striated muscles . Histochemistry and Cell Biology . 130 . 1 . 91–103 . Jul 2008 . 18350308 . 10.1007/s00418-008-0413-z . 35469988 .
  12. Pernigo S, Fukuzawa A, Bertz M, Holt M, Rief M, Steiner RA, Gautel M . 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 . 107 . 7 . 2908–13 . Feb 2010 . 20133654 . 10.1073/pnas.0913736107 . 2814874. 2010PNAS..107.2908P . free .
  13. Lange S, Perera S, Teh P, Chen J . Obscurin and KCTD6 regulate cullin-dependent small ankyrin-1 (sAnk1.5) protein turnover . Molecular Biology of the Cell . 23 . 13 . 2490–504 . Jul 2012 . 22573887 . 10.1091/mbc.E12-01-0052 . 3386213.
  14. Bagnato P, Barone V, Giacomello E, Rossi D, Sorrentino V . 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 . 160 . 2 . 245–53 . Jan 2003 . 12527750 . 10.1083/jcb.200208109 . 2172649.
  15. Kontrogianni-Konstantopoulos A, Jones EM, Van Rossum DB, Bloch RJ . Obscurin is a ligand for small ankyrin 1 in skeletal muscle . Molecular Biology of the Cell . 14 . 3 . 1138–48 . Mar 2003 . 12631729 . 10.1091/mbc.E02-07-0411 . 151585.
  16. Borisov AB, Kontrogianni-Konstantopoulos A, Bloch RJ, Westfall MV, Russell MW . 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 . Sep 2004 . 15314079 . 10.1369/jhc.3A6183.2004 . free .
  17. Borisov AB, Raeker MO, Kontrogianni-Konstantopoulos A, Yang K, Kurnit DM, Bloch RJ, Russell MW . 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 . Oct 2003 . 14550291 . 10.1016/j.bbrc.2003.09.035.
  18. Borisov AB, Martynova MG, Russell MW . Early incorporation of obscurin into nascent sarcomeres: implication for myofibril assembly during cardiac myogenesis . Histochemistry and Cell Biology . 129 . 4 . 463–78 . Apr 2008 . 18219491 . 10.1007/s00418-008-0378-y . 2761667.
  19. Borisov AB, Sutter SB, Kontrogianni-Konstantopoulos A, Bloch RJ, Westfall MV, Russell MW . 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 . Mar 2006 . 16205939 . 10.1007/s00418-005-0069-x . 2027.42/47398 . 13623244 . free .
  20. Hu LY, Kontrogianni-Konstantopoulos A . The kinase domains of obscurin interact with intercellular adhesion proteins . FASEB Journal . 27 . 5 . 2001–12 . May 2013 . 23392350 . 10.1096/fj.12-221317 . free . 3633816.
  21. Makarenko I, Opitz CA, Leake MC, Neagoe C, Kulke M, Gwathmey JK, del Monte F, Hajjar RJ, Linke WA . Matthew Kulke . 6 . Passive stiffness changes caused by upregulation of compliant titin isoforms in human dilated cardiomyopathy hearts . Circulation Research . 95 . 7 . 708–16 . October 2004 . 15345656 . 10.1161/01.RES.0000143901.37063.2f . free .
  22. Arimura T, Matsumoto Y, Okazaki O, Hayashi T, Takahashi M, Inagaki N, Hinohara K, Ashizawa N, Yano K, Kimura A . 6 . Structural analysis of obscurin gene in hypertrophic cardiomyopathy . Biochemical and Biophysical Research Communications . 362 . 2 . 281–7 . October 2007 . 17716621 . 10.1016/j.bbrc.2007.07.183 .
  23. Fukuzawa A, Koch D, Grover S, Rees M, Gautel M . When is an obscurin variant pathogenic? The impact of Arg4344Gln and Arg4444Trp variants on protein-protein interactions and protein stability . Human Molecular Genetics . 30 . 12 . 1131–1141 . June 2021 . 33438037 . 8188405 . 10.1093/hmg/ddab010 .
  24. Fukuzawa A, Koch D, Grover S, Rees M, Gautel M . When is an obscurin variant pathogenic? The impact of Arg4344Gln and Arg4444Trp variants on protein-protein interactions and protein stability . Human Molecular Genetics . 30 . 12 . 1131–1141 . June 2021 . 33438037 . 8188405 . 10.1093/hmg/ddab010 .
  25. Manrai AK, Funke BH, Rehm HL, Olesen MS, Maron BA, Szolovits P, Margulies DM, Loscalzo J, Kohane IS . 6 . Genetic Misdiagnoses and the Potential for Health Disparities . The New England Journal of Medicine . 375 . 7 . 655–65 . August 2016 . 27532831 . 5292722 . 10.1056/NEJMsa1507092 .
  26. Fukuzawa A, Lange S, Holt M, Vihola A, Carmignac V, Ferreiro A, Udd B, Gautel M . 6 . Interactions with titin and myomesin target obscurin and obscurin-like 1 to the M-band: implications for hereditary myopathies . Journal of Cell Science . 121 . 11 . 1841–51 . June 2008 . 18477606 . 10.1242/jcs.028019 . free .
  27. Pernigo S, Fukuzawa A, Pandini A, Holt M, Kleinjung J, Gautel M, Steiner RA . 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 . Feb 2015 . 25490259 . 10.1016/j.jmb.2014.11.019 . free .
  28. Bang ML, Centner T, Fornoff F, Geach AJ, Gotthardt M, McNabb M, Witt CC, Labeit D, Gregorio CC, Granzier H, Labeit S . 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 . Nov 2001 . 11717165 . 10.1161/hh2301.100981. free .
  29. Kontrogianni-Konstantopoulos A, Jones EM, Van Rossum DB, Bloch RJ . Obscurin is a ligand for small ankyrin 1 in skeletal muscle . Molecular Biology of the Cell . 14 . 3 . 1138–48 . Mar 2003 . 12631729 . 151585 . 10.1091/mbc.E02-07-0411 .
  30. Busby B, Oashi T, Willis CD, Ackermann MA, Kontrogianni-Konstantopoulos A, Mackerell AD, Bloch RJ . Electrostatic interactions mediate binding of obscurin to small ankyrin 1: biochemical and molecular modeling studies . Journal of Molecular Biology . 408 . 2 . 321–34 . Apr 2011 . 21333652 . 10.1016/j.jmb.2011.01.053 . 3367564.
  31. Cunha SR, Mohler PJ . Obscurin targets ankyrin-B and protein phosphatase 2A to the cardiac M-line . The Journal of Biological Chemistry . 283 . 46 . 31968–80 . Nov 2008 . 18782775 . 10.1074/jbc.M806050200 . 2581558. free .

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