Nebulette

NEBL
Available structures
PDB	Ortholog search: PDBe RCSB
List of PDB id codes
	4F14
Identifiers
Aliases	NEBL, nebulette, LASP2, LNEBL
External IDs	OMIM: 605491; MGI: 1921353; HomoloGene: 31379; GeneCards: NEBL; OMA:NEBL - orthologs
Gene location (Human)
Chr.	Chromosome 10 (human)
End	21,174,187 bp
Gene location (Mouse)
Chr.	Chromosome 2 (mouse)
End	17,731,464 bp
RNA expression pattern
	Top expressed in
	right ventricle; ; myocardium; ; myocardium of left ventricle; ; optic nerve; ; cardiac muscle tissue of right atrium; ; apex of heart; ; glomerulus; ; metanephric glomerulus; ; right auricle; ; Brodmann area 23;
	Top expressed in
	interventricular septum; ; atrium; ; myocardium of ventricle; ; atrioventricular valve; ; vestibular sensory epithelium; ; ciliary body; ; right lung lobe; ; left lung lobe; ; mammillary body; ; deep cerebellar nuclei;
	More reference expression data
	n/a
Gene ontology
Molecular function	filamin binding; cytoskeletal protein binding; actin filament binding; actin binding; structural constituent of muscle; tropomyosin binding; protein binding;
Cellular component	cytoplasm; Z disc; extracellular exosome; I band; stress fiber;
Biological process	cardiac muscle thin filament assembly;
	Sources:Amigo / QuickGO
Orthologs
	10529
	74103
	ENSG00000078114
	ENSMUSG00000053702
	O76041; Q5JUU7
	Q9DC07; Q0II04
	NM_001173484; NM_006393; NM_016365; NM_213569
	NM_028757; NM_001362722
NP_001166955; NP_006384; NP_998734; NP_001364251; NP_001364252;
	NP_001364253; NP_001364254; NP_001364255; NP_001364256; NP_001364257
	NP_083033.1; NP_083033; NP_001349651
	Wikidata
View/Edit Human	View/Edit Mouse

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.^[5]^[6] 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 S Dxx Y K motif.^[7] 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.^[8] 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).^[9] Nebulette interacts with actin, tropomyosin, alpha-actinin.^[10] Xin, and XIRP2.^[11]

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.^[12] Normal expression of nebulette is essential for the assembly and contractile function of myofibrils.^[13] 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.^[14]^[15]

Clinical significance

Mutations in the NEBL gene have been associated with dilated cardiomyopathy.^[16] Studies in transgenic mice have supported their causative role in endocardial fibroelastosis and dilated cardiomyopathy.^[17]

References

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000078114 – Ensembl, May 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000053702 – Ensembl, May 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Nebulette". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB). Archived from the original on 2016-03-03. Retrieved 2015-03-20.
^ 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.{{cite journal}}: CS1 maint: numeric names: authors list (link)
^ 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. S2CID 33047653.
^ 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. PMC 3014390. PMID 20951588.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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. S2CID 4564490.
^ 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. PMC 2957670. PMID 20951326.
^ 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.