Nebulette Explained

Nebulette is a cardiac-specific isoform belonging to the nebulin family of proteins. It is encoded by the NEBL gene. This family is composed of 5 members: nebulette, nebulin, N-RAP, LASP-1 and LASP-2. Nebulette localizes to Z-discs of cardiac muscle and appears to regulate the length of actin thin filaments.

Structure

Nebulette is a 116.4 kDa protein composed of 1014 amino acids.[1] [2] As a member of the nebulin family of proteins, nebulette is characterized by 35 amino acid stretches of ‘‘nebulin repeats’’, which are actin binding domains containing a conserved SDxxYK motif.[3] Like nebulin, nebulette has an acidic region with unknown structure at its N-terminus, and a serine-rich region adjacent to an SH3 domain at its C-terminus.[4] Though nebulette shares structural features with nebulin, nebulin is expressed preferentially in skeletal muscle and has an enormous size (600-900 kDa), while nebulette is expressed in cardiac muscle at Z-disc regions and is significantly smaller (roughly 1/6 of the size).[5] Nebulette interacts with actin, tropomyosin, alpha-actinin.[6] Xin, and XIRP2.[7]

Function

Nebulette was identified in 1995 by Moncman and Wang using primary cultures of chicken embryonic cardiomyocytes by immunoprecipitations with certain anti-nebulin monoclonal antibodies.[8] Normal expression of nebulette is essential for the assembly and contractile function of myofibrils.[9] Specifically, nebulette appears to regulate the stability and length of actin thin filaments, as well as beating frequencies of cardiomyocytes; reduction of full-length nebulette protein in cardiomyocytes resulted in reduced thin filament lengths, depressed beating frequencies and loss of thin filament regulatory proteins troponin I and tropomyosin.[10] [11]

Clinical significance

Mutations in the NEBL gene have been associated with dilated cardiomyopathy.[12] Studies in transgenic mice have supported their causative role in endocardial fibroelastosis and dilated cardiomyopathy.[13]

Further reading

External links

Notes and References

  1. Web site: Nebulette . Cardiac Organellar Protein Atlas Knowledgebase (COPaKB) . 2015-03-20 . 2016-03-03 . https://web.archive.org/web/20160303234506/http://www.heartproteome.org/copa/ProteinInfo.aspx?QType=Protein%20ID&QValue=O76041 . dead .
  2. 23965338. 4076475. 2013. Zong. N. C.. Integration of cardiac proteome biology and medicine by a specialized knowledgebase. Circulation Research. 113. 9. 1043–53. Li. H. Li. H. Lam. M. P.. Jimenez. R. C.. Kim. C. S.. Deng. N. Kim. A. K.. Choi. J. H.. Zelaya. I. Liem. D. Meyer. D. Odeberg. J. Fang. C. Lu. H. J.. Xu. T. Weiss. J. Duan. H. Uhlen. M. Yates Jr. 3rd. Apweiler. R. Ge. J. Hermjakob. H. Ping. P. 10.1161/CIRCRESAHA.113.301151.
  3. Labeit S, Gibson T, Lakey A, Leonard K, Zeviani M, Knight P, Wardale J, Trinick J . Evidence that nebulin is a protein-ruler in muscle thin filaments . FEBS Letters . 282 . 2 . May 1991 . 2037050 . 10.1016/0014-5793(91)80503-u . 313–6. 33047653 . free .
  4. Pappas CT, Bliss KT, Zieseniss A, Gregorio CC . The Nebulin family: an actin support group . Trends in Cell Biology . 21 . 1 . Jan 2011 . 20951588 . 10.1016/j.tcb.2010.09.005 . 29–37 . 3014390.
  5. Moncman CL, Wang K . Nebulette: a 107 kD nebulin-like protein in cardiac muscle . Cell Motility and the Cytoskeleton . 32 . 3 . 8581976 . 10.1002/cm.970320305 . 1995 . 205–25.
  6. Moncman CL, Wang K . Functional dissection of nebulette demonstrates actin binding of nebulin-like repeats and Z-line targeting of SH3 and linker domains . Cell Motility and the Cytoskeleton . 44 . 1 . 10470015 . 10.1002/(SICI)1097-0169(199909)44:1<1::AID-CM1>3.0.CO;2-8 . 1999 . 1–22.
  7. 23985323. 3810769. 2013. Eulitz. S. Identification of Xin-repeat proteins as novel ligands of the SH3 domains of nebulin and nebulette and analysis of their interaction during myofibril formation and remodeling. Molecular Biology of the Cell. 24. 20. 3215–26. Sauer. F. Pelissier. M. C.. Boisguerin. P. Molt. S. Schuld. J. Orfanos. Z. Kley. R. A.. Volkmer. R. Wilmanns. M. Kirfel. G. Van Der Ven. P. F.. Fürst. D. O.. 10.1091/mbc.E13-04-0202.
  8. Moncman CL, Wang K . Nebulette: a 107 kD nebulin-like protein in cardiac muscle . Cell Motility and the Cytoskeleton . 32 . 3 . 205–25 . 1995 . 8581976 . 10.1002/cm.970320305 .
  9. Moncman CL, Wang K . Targeted disruption of nebulette protein expression alters cardiac myofibril assembly and function . Experimental Cell Research . 273 . 2 . 204–18 . Feb 2002 . 11822876 . 10.1006/excr.2001.5423 .
  10. Bonzo JR, Norris AA, Esham M, Moncman CL . The nebulette repeat domain is necessary for proper maintenance of tropomyosin with the cardiac sarcomere . Experimental Cell Research . 314 . 19 . Nov 2008 . 18823973 . 10.1016/j.yexcr.2008.09.001 . 3519–30.
  11. Moncman CL, Wang K . Targeted disruption of nebulette protein expression alters cardiac myofibril assembly and function . Experimental Cell Research . 273 . 2 . Feb 2002 . 11822876 . 10.1006/excr.2001.5423 . 204–18.
  12. Arimura T, Nakamura T, Hiroi S, Satoh M, Takahashi M, Ohbuchi N, Ueda K, Nouchi T, Yamaguchi N, Akai J, Matsumori A, Sasayama S, Kimura A . Characterization of the human nebulette gene: a polymorphism in an actin-binding motif is associated with nonfamilial idiopathic dilated cardiomyopathy . Human Genetics . 107 . 5 . Nov 2000 . 11140941 . 440–51 . 10.1007/s004390000389. 4564490 .
  13. Purevjav E, Varela J, Morgado M, Kearney DL, Li H, Taylor MD, Arimura T, Moncman CL, McKenna W, Murphy RT, Labeit S, Vatta M, Bowles NE, Kimura A, Boriek AM, Towbin JA . Nebulette mutations are associated with dilated cardiomyopathy and endocardial fibroelastosis . Journal of the American College of Cardiology . 56 . 18 . Oct 2010 . 20951326 . 10.1016/j.jacc.2010.05.045 . 1493–502 . 2957670.
  14. Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS, Deng N, Kim AK, Choi JH, Zelaya I, Liem D, Meyer D, Odeberg J, Fang C, Lu HJ, Xu T, Weiss J, Duan H, Uhlen M, Yates JR, Apweiler R, Ge J, Hermjakob H, Ping P . Integration of cardiac proteome biology and medicine by a specialized knowledgebase . Circulation Research . 113 . 9 . Oct 2013 . 23965338 . 10.1161/CIRCRESAHA.113.301151 . 4076475 . 1043–1053.

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