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The ''NEBL'' [[gene]] encodes the [[protein]] '''Nebulette''', a [[cardiac]]-specific [[isoform]] belonging to the [[nebulin]] family of [[protein]]s. This family is composed of 5 members: nebulette, [[NEB|nebulin]], [[NRAP|N-RAP]], [[LASP1|LASP-1]] and LASP-2. Nebulette localizes to [[sarcomere|Z-discs]] of [[cardiac muscle]] and appears to regulate the length of [[ACTC1|actin]] thin filaments.
The ''NEBL'' [[gene]] encodes the [[protein]] '''Nebulette''', a [[cardiac]]-specific [[isoform]] belonging to the [[nebulin]] family of [[protein]]s. This family is composed of 5 members: nebulette, [[NEB|nebulin]], [[NRAP|N-RAP]], [[LASP1|LASP-1]] and LASP-2. Nebulette localizes to [[sarcomere|Z-discs]] of [[cardiac muscle]] and appears to regulate the length of [[ACTC1|actin]] thin filaments.


==Structure==
== Structure ==
⚫
Nebulette is a 116.4 kDa protein comprised of 1014 amino acids ([http://www.heartproteome.org/copa/ProteinInfo.aspx?QType=Protein%20ID&QValue=O76041 See human NEBL sequence features here]). 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 [[serine|S]][[aspartate|D]]xx[[tyrosine|Y]][[lysine|K]] motif (PMID 2037050). 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 (PMID 20951588). 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 [[sarcomere|Z-disc]] regions and is significantly smaller (roughly 1/6 of the size) (PMID 8581976). Nebulette interacts with [[ACTC1|actin]], [[TPM1|tropomyosin]] and [[ACTN2|alpha-actinin]] (PMID 10470015).


⚫
Nebulette is a 116.4 kDa protein comprised of 1014 amino acids ([http://www.heartproteome.org/copa/ProteinInfo.aspx?QType=Protein%20ID&QValue=O76041 See human NEBL sequence features here]). 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 [[serine|S]][[aspartate|D]]xx[[tyrosine|Y]][[lysine|K]] motif (PMID 2037050). 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 (PMID 20951588). 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 [[sarcomere|Z-disc]] regions and is significantly smaller (roughly 1/6 of the size) (PMID 8581976). Nebulette interacts with [[ACTC1|actin]], [[TPM1|tropomyosin]] and [[ACTN2|alpha-actinin]].<ref>{{vcite2 journal | vauthors = Moncman CL, Wang K | title = Functional dissection of nebulette demonstrates actin binding of nebulin-like repeats and Z-line targeting of SH3 and linker domains | journal = Cell Motility and the Cytoskeleton | volume = 44 | issue = 1 | pmid = 10470015 | doi = 10.1002/(SICI)1097-0169(199909)44:1<1::AID-CM1>3.0.CO;2-8 }</ref>
⚫
==Function==
⚫
Nebulette was identified in 1995 by Moncman and Wang using primary cultures of chicken embryonic [[cardiomyocyte]]s by [[immunoprecipitation]]s with certain anti-nebulin [[monoclonal antibodies]].<ref name="moncman">{{cite journal |author=Moncman & Wang |title=Nebulette: a 107 kD nebulin-like protein in cardiac muscle |journal=[[Cell Motil Cytoskeleton]] |volume=32 |issue=3 |pages=205–25 |year=1995 |pmid=8581976 |doi=10.1002/cm.970320305 |last2=Wang |first2=K }}</ref> Normal expression of nebulette is essential for the assembly and [[muscle contraction|contractile function]] of [[myofibril]]s.<ref name="moncman2">{{cite journal |author=Moncman & Wang |title=Targeted disruption of nebulette protein expression alters cardiac myofibril assembly and function |journal=Exp Cell Res |volume=273 |issue=2 |pages=204–18 |year=2002 |pmid=11822876 |doi=10.1006/excr.2001.5423 |last2=Wang |first2=K }}</ref> 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 [[TNNI3|troponin I]] and [[TPM1|tropomyosin]] (PMID 18823973) (PMID 11822876).


⚫
== Function ==
⚫
==Clinical Significance==

Mutations in the ''NEBL'' gene have been associated with [[dilated cardiomyopathy]] (DCM) (PMID 11140941). Studies in transgenic mice have supported their causative role in endocardial fibroelastosis and [[dilated cardiomyopathy|DCM]] (PMID 20951326).
⚫
Nebulette was identified in 1995 by Moncman and Wang using primary cultures of chicken embryonic [[cardiomyocyte]]s by [[immunoprecipitation]]s with certain anti-nebulin [[monoclonal antibodies]].<ref name="moncman">{{vcite2 journal | vauthors = Moncman CL, Wang K | title = Nebulette: a 107 kD nebulin-like protein in cardiac muscle | journal = Cell Motility and the Cytoskeleton | volume = 32 | issue = 3 | pages = 205–25 | year = 1995 | pmid = 8581976 | doi = 10.1002/cm.970320305 | first2 = K }}</ref> Normal expression of nebulette is essential for the assembly and [[muscle contraction|contractile function]] of [[myofibril]]s.<ref name="moncman2">{{vcite2 journal | vauthors = Moncman CL, Wang K | title = Targeted disruption of nebulette protein expression alters cardiac myofibril assembly and function | journal = Experimental Cell Research | volume = 273 | issue = 2 | pages = 204–18 | date = Feb 2002 | pmid = 11822876 | doi = 10.1006/excr.2001.5423 }}</ref> 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 [[TNNI3|troponin I]] and [[TPM1|tropomyosin]].<ref>{{vcite2 journal | vauthors = Bonzo JR, Norris AA, Esham M, Moncman CL | title = The nebulette repeat domain is necessary for proper maintenance of tropomyosin with the cardiac sarcomere | journal = Experimental Cell Research | volume = 314 | issue = 19 | date = Nov 2008 | pmid = 18823973 | doi = 10.1016/j.yexcr.2008.09.001 }}</ref><ref>{{vcite2 journal | vauthors = Moncman CL, Wang K | title = Targeted disruption of nebulette protein expression alters cardiac myofibril assembly and function | journal = Experimental Cell Research | volume = 273 | issue = 2 | date = Feb 2002 | pmid = 11822876 | doi = 10.1006/excr.2001.5423 }}</ref>

⚫
== Clinical significance ==

Mutations in the ''NEBL'' gene have been associated with [[dilated cardiomyopathy]].<ref>{{vcite2 journal | vauthors = 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 | title = Characterization of the human nebulette gene: a polymorphism in an actin-binding motif is associated with nonfamilial idiopathic dilated cardiomyopathy | journal = Human Genetics | volume = 107 | issue = 5 | date = Nov 2000 | pmid = 11140941 }}</ref> Studies in transgenic mice have supported their causative role in endocardial fibroelastosis and [[dilated cardiomyopathy|DCM]].<ref>{{vcite2 journal | vauthors = 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 | title = Nebulette mutations are associated with dilated cardiomyopathy and endocardial fibroelastosis | journal = Journal of the American College of Cardiology | volume = 56 | issue = 18 | date = Oct 2010 | pmid = 20951326 | doi = 10.1016/j.jacc.2010.05.045 }}</ref>


== References ==
== References ==
{{Reflist}}
{{Reflist|33em}}


== External links ==
== External links ==
* [http://www.heartproteome.org/copa/ProteinInfo.aspx?QType=Protein%20ID&QValue=O76041 Mass spectrometry characterization of NEBL at COPaKB] (PMID 23965338)
* [http://www.heartproteome.org/copa/ProteinInfo.aspx?QType=Protein%20ID&QValue=O76041 Mass spectrometry characterization of NEBL at COPaKB<ref>{{vcite2 journal | vauthors = 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 | title = Integration of cardiac proteome biology and medicine by a specialized knowledgebase | journal = Circulation Research | volume = 113 | issue = 9 | date = Oct 2013 | pmid = 23965338 | doi = 10.1161/CIRCRESAHA.113.301151 }}</ref>
* {{MeshName|nebulette}}
* {{MeshName|nebulette}}


Revision as of 21:24, 21 March 2015

NEBL
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesNEBL, nebulette, LASP2, LNEBL
External IDsOMIM: 605491; MGI: 1921353; HomoloGene: 31379; GeneCards: NEBL; OMA:NEBL - orthologs
Orthologs
SpeciesHumanMouse
Entrez

10529

74103

Ensembl

ENSG00000078114

ENSMUSG00000053702

UniProt

O76041
Q5JUU7

Q9DC07
Q0II04

RefSeq (mRNA)

NM_001173484
NM_006393
NM_016365
NM_213569

NM_028757
NM_001362722

RefSeq (protein)

NP_083033.1
NP_083033
NP_001349651

Location (UCSC)Chr 10: 20.78 – 21.17 MbChr 2: 17.34 – 17.73 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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 comprised of 1014 amino acids (See human NEBL sequence features here). 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 (PMID 2037050). 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 (PMID 20951588). 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) (PMID 8581976). Nebulette interacts with actin, tropomyosin and alpha-actinin.[5]

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.[6] Normal expression of nebulette is essential for the assembly and contractile function of myofibrils.[7] 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.[8][9]

Clinical significance

Mutations in the NEBL gene have been associated with dilated cardiomyopathy.[10] Studies in transgenic mice have supported their causative role in endocardial fibroelastosis and DCM.[11]

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000078114 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000053702 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ {{vcite2 journal | vauthors = Moncman CL, Wang K | title = Functional dissection of nebulette demonstrates actin binding of nebulin-like repeats and Z-line targeting of SH3 and linker domains | journal = Cell Motility and the Cytoskeleton | volume = 44 | issue = 1 | pmid = 10470015 | doi = 10.1002/(SICI)1097-0169(199909)44:1<1::AID-CM1>3.0.CO;2-8 }
  6. ^ "Nebulette: a 107 kD nebulin-like protein in cardiac muscle". Cell Motility and the Cytoskeleton. 32 (3): 205–25. 1995. doi:10.1002/cm.970320305. PMID 8581976. {{cite journal}}: |first2= missing |last2= (help); More than one of author-name-list parameters specified (help)
  7. ^ 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.
  8. ^ 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). doi:10.1016/j.yexcr.2008.09.001. PMID 18823973.
  9. ^ Moncman CL, Wang K (Feb 2002). "Targeted disruption of nebulette protein expression alters cardiac myofibril assembly and function". Experimental Cell Research. 273 (2). doi:10.1006/excr.2001.5423. PMID 11822876.
  10. ^ 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). PMID 11140941.
  11. ^ 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). doi:10.1016/j.jacc.2010.05.045. PMID 20951326.
  1. ^ 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). doi:10.1161/CIRCRESAHA.113.301151. PMID 23965338.
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