Nebulette

Nebulin

Solution structure of the SH3 domain from human nebulin.[1]
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols NEB ; NEB177D; NEM2
External IDs OMIM: 161650 HomoloGene: 136285 GeneCards: NEB Gene
Orthologs
Species Human Mouse
Entrez 4703 17996
Ensembl ENSG00000183091 ENSMUSG00000026950
UniProt P20929 n/a
RefSeq (mRNA) NM_001164507 NM_010889
RefSeq (protein) NP_001157979 NP_035019
Location (UCSC) Chr 2:
151.49 – 151.73 Mb		 Chr 2:
52.14 – 52.34 Mb
PubMed search

The NEBL gene encodes the protein Nebulette, a cardiac-specific isoform belonging to the nebulin family of proteins. 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.[2][3] 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.[4] 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.[5] 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).[6] Nebulette interacts with actin, tropomyosin, alpha-actinin.[7] Xin, and XIRP2.[8]

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.[9] Normal expression of nebulette is essential for the assembly and contractile function of myofibrils.[10] 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.[11][12]

Clinical significance

Mutations in the NEBL gene have been associated with dilated cardiomyopathy.[13] Studies in transgenic mice have supported their causative role in endocardial fibroelastosis and dilated cardiomyopathy.[14]

Further reading

References

  1. ↑ PDB: 1NEB​; Politou AS, Millevoi S, Gautel M, Kolmerer B, Pastore A (February 1998). "SH3 in muscles: solution structure of the SH3 domain from nebulin". J. Mol. Biol. 276 (1): 189–202. doi:10.1006/jmbi.1997.1521. PMID 9514727.
  2. ↑ "Nebulette". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB).
  3. ↑ Zong, N. C.; 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 (2013). "Integration of cardiac proteome biology and medicine by a specialized knowledgebase". Circulation Research 113 (9): 1043–53. doi:10.1161/CIRCRESAHA.113.301151. PMC 4076475. PMID 23965338.
  4. ↑ Labeit S, Gibson T, Lakey A, Leonard K, Zeviani M, Knight P, Wardale J, Trinick J (May 1991). "Evidence that nebulin is a protein-ruler in muscle thin filaments". FEBS Letters 282 (2): 313–6. doi:10.1016/0014-5793(91)80503-u. PMID 2037050.
  5. ↑ Pappas CT, Bliss KT, Zieseniss A, Gregorio CC (Jan 2011). "The Nebulin family: an actin support group". Trends in Cell Biology 21 (1): 29–37. doi:10.1016/j.tcb.2010.09.005. PMID 20951588.
  6. ↑ Moncman CL, Wang K (1995). "Nebulette: a 107 kD nebulin-like protein in cardiac muscle". Cell Motility and the Cytoskeleton 32 (3): 205–25. doi:10.1002/cm.970320305. PMID 8581976.
  7. ↑ Moncman CL, Wang K (1999). "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): 1–22. doi:10.1002/(SICI)1097-0169(199909)44:1<1::AID-CM1>3.0.CO;2-8. PMID 10470015.
  8. ↑ Eulitz, S; 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. (2013). "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. doi:10.1091/mbc.E13-04-0202. PMC 3810769. PMID 23985323.
  9. ↑ Moncman CL, Wang K (1995). "Nebulette: a 107 kD nebulin-like protein in cardiac muscle". Cell Motility and the Cytoskeleton 32 (3): 205–25. doi:10.1002/cm.970320305. PMID 8581976.
  10. ↑ Moncman CL, Wang K (Feb 2002). "Targeted disruption of nebulette protein expression alters cardiac myofibril assembly and function". Experimental Cell Research 273 (2): 204–18. doi:10.1006/excr.2001.5423. PMID 11822876.
  11. ↑ Bonzo JR, Norris AA, Esham M, Moncman CL (Nov 2008). "The nebulette repeat domain is necessary for proper maintenance of tropomyosin with the cardiac sarcomere". Experimental Cell Research 314 (19): 3519–30. doi:10.1016/j.yexcr.2008.09.001. PMID 18823973.
  12. ↑ Moncman CL, Wang K (Feb 2002). "Targeted disruption of nebulette protein expression alters cardiac myofibril assembly and function". Experimental Cell Research 273 (2): 204–18. doi:10.1006/excr.2001.5423. PMID 11822876.
  13. ↑ 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 (Nov 2000). "Characterization of the human nebulette gene: a polymorphism in an actin-binding motif is associated with nonfamilial idiopathic dilated cardiomyopathy". Human Genetics 107 (5): 440–51. doi:10.1007/s004390000389. PMID 11140941.
  14. ↑ 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 (Oct 2010). "Nebulette mutations are associated with dilated cardiomyopathy and endocardial fibroelastosis". Journal of the American College of Cardiology 56 (18): 1493–502. doi:10.1016/j.jacc.2010.05.045. PMID 20951326.
  15. ↑ 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 (Oct 2013). "Integration of cardiac proteome biology and medicine by a specialized knowledgebase". Circulation Research 113 (9): 1043–1053. doi:10.1161/CIRCRESAHA.113.301151. PMC 4076475. PMID 23965338.

External links

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