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Gene Review

NEB  -  nebulin

Homo sapiens

Synonyms: NEB177D, NEM2, Nebulin
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Disease relevance of NEB


High impact information on NEB

  • Additional isoforms, including products of tropomyosin, myosin light chain 1 fast, troponin T, titin, and nebulin genes, can be generated from the same gene through alternative splicing or use of alternative promoters [6].
  • Is nebulin the defective gene product in Duchenne muscular dystrophy [7]?
  • The individual units of the sarcomere, the basic contractile unit of myofibrils, include the thin, thick, titin, and nebulin filaments [8].
  • The amino acid sequence that is predicted from this portion of the DMD gene indicates that the protein product might serve a structural role in muscle, but the abundance and tissue distribution of the messenger RNA suggests that the DMD protein is not nebulin [9].
  • The mechanisms responsible for specifying the characteristic filament lengths in these systems are more elusive and may include strict control of the relative amounts of actin filament capping proteins and side-binding proteins, molecular templates (e.g. tropomyosin and nebulin) and/or verniers (e.g. tropomyosin) [10].

Chemical compound and disease context of NEB


Biological context of NEB


Anatomical context of NEB

  • Nebulin is a giant protein ( approximately 800 kDa) in skeletal muscle that has been proposed to act as a molecular ruler to specify the thin filament lengths characteristic of different muscles [14].
  • Nebulin was integrated in these young myofibrils at a later developmental stage [15].
  • Nebulin, a giant modular protein from muscle, is thought to act as a molecular ruler in sarcomere assembly [16].
  • After nebulin becomes organized into a striated pattern, actin filaments separate across the A-band and form thin filaments of uniform length [13].
  • In cultures treated with the microtubule stabilizing drug taxol, the amount of stress fibers and nascent I-bands was greatly diminished as previously reported by others; however, nebulin was found associated with myofibrils in a mature striated distribution [13].

Associations of NEB with chemical compounds

  • We have employed the strategy of using ethyl methane sulfonate and taxol to perturb myofibril assembly to examine interactions critical for the addition of nebulin to the developing sarcomeres [13].
  • Cultured embryonic chicken skeletal muscle cells microinjected with rhodamine (rh)-labeled actin were stained with antibodies against nebulin and connectin (titin) [17].
  • To define molecular interfaces between nebulin and CaM, we thiolated lysines of CaM and ND66, a four-module cloned fragment from the C-terminus of nebulin, with 2-iminothiolane and cross-linked the complex with dibromobimane, which alkylates thiol pairs within approximately 6 A of each other to form a fluorescent adduct [18].
  • The serine-rich linker region of nebulette has previously been shown to serve just such a purpose by targeting the association of the nebulin modules to the cardiac Z-line in cultured cardiomyocytes [19].
  • The most common autosomal recessive form affecting infants (NEM2) links to chromosome 2q, and is caused by mutations in the gene for nebulin [20].

Physical interactions of NEB

  • The N-terminal end of nebulin interacts with tropomodulin at the pointed ends of the thin filaments [14].
  • Resolution of the approximately 1.0 microm polarized alpha-actin/nebulin/tropomyosin/troponin thin filament complexes occurred subsequent to the maturation of Z-bands into a dense tetragonal configuration [21].
  • Our data are consistent with a model that desmin attaches directly to the Z-line through its interaction with the nebulin repeats M163-M170 [22].
  • Functional dissection of nebulette demonstrates actin binding of nebulin-like repeats and Z-line targeting of SH3 and linker domains [23].
  • Western blots of human skeletal muscle biopsy samples were probed with biotinylated calmodulin; nebulin was identified as a prominent high-molecular-mass calmodulin-binding protein but dystrophin did not bind detectable amounts of biotinylated calmodulin [24].

Co-localisations of NEB


Other interactions of NEB


Analytical, diagnostic and therapeutic context of NEB


  1. Refined localisation of the genes for nebulin and titin on chromosome 2q allows the assignment of nebulin as a candidate gene for autosomal recessive nemaline myopathy. Pelin, K., Ridanpää, M., Donner, K., Wilton, S., Krishnarajah, J., Laing, N., Kolmerer, B., Millevoi, S., Labeit, S., de la Chapelle, A., Wallgren-Petterson, C. Eur. J. Hum. Genet. (1997) [Pubmed]
  2. Nebulin and titin expression in Duchenne muscular dystrophy appears normal. Fürst, D., Nave, R., Osborn, M., Weber, K., Bardosi, A., Archidiacono, N., Ferro, M., Romano, V., Romeo, G. FEBS Lett. (1987) [Pubmed]
  3. Cloning, expression, and protein interaction of human nebulin fragments composed of varying numbers of sequence modules. Jin, J.P., Wang, K. J. Biol. Chem. (1991) [Pubmed]
  4. Each actin subunit has three nebulin binding sites: implications for steric blocking. Lukoyanova, N., VanLoock, M.S., Orlova, A., Galkin, V.E., Wang, K., Egelman, E.H. Curr. Biol. (2002) [Pubmed]
  5. Sarcomeric disorganization in post-mortem fish muscles. Astier, C., Labbe, J.P., Roustan, C., Benyamin, Y. Comp. Biochem. Physiol., B (1991) [Pubmed]
  6. Molecular diversity of myofibrillar proteins: gene regulation and functional significance. Schiaffino, S., Reggiani, C. Physiol. Rev. (1996) [Pubmed]
  7. Is nebulin the defective gene product in Duchenne muscular dystrophy? Wood, D.S., Zeviani, M., Prelle, A., Bonilla, E., Salviati, G., Miranda, A.F., DiMauro, S., Rowland, L.P. N. Engl. J. Med. (1987) [Pubmed]
  8. Striated muscle cytoarchitecture: an intricate web of form and function. Clark, K.A., McElhinny, A.S., Beckerle, M.C., Gregorio, C.C. Annu. Rev. Cell Dev. Biol. (2002) [Pubmed]
  9. Conservation of the Duchenne muscular dystrophy gene in mice and humans. Hoffman, E.P., Monaco, A.P., Feener, C.C., Kunkel, L.M. Science (1987) [Pubmed]
  10. Regulation of actin filament length in erythrocytes and striated muscle. Fowler, V.M. Curr. Opin. Cell Biol. (1996) [Pubmed]
  11. Complete genomic structure of the human nebulin gene and identification of alternatively spliced transcripts. Donner, K., Sandbacka, M., Lehtokari, V.L., Wallgren-Pettersson, C., Pelin, K. Eur. J. Hum. Genet. (2004) [Pubmed]
  12. Chromosomal localization of the mouse titin gene and its relation to "muscular dystrophy with myositis" and nebulin genes on chromosome 2. Müller-Seitz, M., Kaupmann, K., Labeit, S., Jockusch, H. Genomics (1993) [Pubmed]
  13. Assembly of nebulin into the sarcomeres of avian skeletal muscle. Moncman, C.L., Wang, K. Cell Motil. Cytoskeleton (1996) [Pubmed]
  14. The N-terminal end of nebulin interacts with tropomodulin at the pointed ends of the thin filaments. McElhinny, A.S., Kolmerer, B., Fowler, V.M., Labeit, S., Gregorio, C.C. J. Biol. Chem. (2001) [Pubmed]
  15. Titin aggregates associated with intermediate filaments align along stress fiber-like structures during human skeletal muscle cell differentiation. van der Ven, P.F., Schaart, G., Croes, H.J., Jap, P.H., Ginsel, L.A., Ramaekers, F.C. J. Cell. Sci. (1993) [Pubmed]
  16. The SH3 domain of nebulin binds selectively to type II peptides: theoretical prediction and experimental validation. Politou, A.S., Spadaccini, R., Joseph, C., Brannetti, B., Guerrini, R., Helmer-Citterich, M., Salvadori, S., Temussi, P.A., Pastore, A. J. Mol. Biol. (2002) [Pubmed]
  17. Relation of nebulin and connectin (titin) to dynamics of actin in nascent myofibrils of cultured skeletal muscle cells. Nwe, T.M., Maruyama, K., Shimada, Y. Exp. Cell Res. (1999) [Pubmed]
  18. Mapping protein interfaces with a fluorogenic cross-linker and mass spectrometry: application to nebulin-calmodulin complexes. Sinz, A., Wang, K. Biochemistry (2001) [Pubmed]
  19. Linker region of nebulin family members plays an important role in targeting these molecules to cellular structures. Panaviene, Z., Moncman, C.L. Cell Tissue Res. (2007) [Pubmed]
  20. Abnormalities in the expression of nebulin in chromosome-2 linked nemaline myopathy. Sewry, C.A., Brown, S.C., Pelin, K., Jungbluth, H., Wallgren-Pettersson, C., Labeit, S., Manzur, A., Muntoni, F. Neuromuscul. Disord. (2001) [Pubmed]
  21. Initiation and maturation of I-Z-I bodies in the growth tips of transfected myotubes. Ojima, K., Lin, Z.X., Zhang, Z.Q., Hijikata, T., Holtzer, S., Labeit, S., Sweeney, H.L., Holtzer, H. J. Cell. Sci. (1999) [Pubmed]
  22. Molecular dissection of the interaction of desmin with the C-terminal region of nebulin. Bang, M.L., Gregorio, C., Labeit, S. J. Struct. Biol. (2002) [Pubmed]
  23. Functional dissection of nebulette demonstrates actin binding of nebulin-like repeats and Z-line targeting of SH3 and linker domains. Moncman, C.L., Wang, K. Cell Motil. Cytoskeleton (1999) [Pubmed]
  24. Calmodulin-binding profiles for nebulin and dystrophin in human skeletal muscle. Patel, K., Strong, P.N., Dubowitz, V., Dunn, M.J. FEBS Lett. (1988) [Pubmed]
  25. Interaction of nebulin SH3 domain with titin PEVK and myopalladin: implications for the signaling and assembly role of titin and nebulin. Ma, K., Wang, K. FEBS Lett. (2002) [Pubmed]
  26. Myofibrillogenesis in primary tissue cultures of adult human skeletal muscle: expression of desmin, titin, and nebulin. Behr, T., Fischer, P., Müller-Felber, W., Schmidt-Achert, M., Pongratz, D. The Clinical investigator. (1994) [Pubmed]
  27. Nebulette: a 107 kD nebulin-like protein in cardiac muscle. Moncman, C.L., Wang, K. Cell Motil. Cytoskeleton (1995) [Pubmed]
  28. The organization of titin filaments in the half-sarcomere revealed by monoclonal antibodies in immunoelectron microscopy: a map of ten nonrepetitive epitopes starting at the Z line extends close to the M line. Fürst, D.O., Osborn, M., Nave, R., Weber, K. J. Cell Biol. (1988) [Pubmed]
  29. Evidence for a dominant-negative effect in ACTA1 nemaline myopathy caused by abnormal folding, aggregation and altered polymerization of mutant actin isoforms. Ilkovski, B., Nowak, K.J., Domazetovska, A., Maxwell, A.L., Clement, S., Davies, K.E., Laing, N.G., North, K.N., Cooper, S.T. Hum. Mol. Genet. (2004) [Pubmed]
  30. Titin as a Giant Scaffold for Integrating Stress and Src Homology Domain 3-mediated Signaling Pathways: THE CLUSTERING OF NOVEL OVERLAP LIGAND MOTIFS IN THE ELASTIC PEVK SEGMENT. Ma, K., Forbes, J.G., Gutierrez-Cruz, G., Wang, K. J. Biol. Chem. (2006) [Pubmed]
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