Nebulin

nebulin
Solution structure of the SH3 domain from human nebulin.[1]
Identifiers
Symbol	NEB
Alt. symbols	NEM2
Entrez	4703
HUGO	7720
OMIM	161650
PDB	1NEB
RefSeq	NM_004543
UniProt	P20929
Other data
Locus	Chr. 2 q22

Nebulin is an actin-binding protein which is localized to the I-band of the sarcomeres in skeletal muscle. It is a very large protein (600-900 kDa) and binds as many as 200 actin monomers. Because its length is proportional to thin filament length, it is believed that nebulin acts as a thin filament "ruler" and regulates thin filament length during sarcomere assembly.^[2] Other functions of nebulin, such as a role in cell signaling, remain uncertain.

Nebulin has also been shown to regulate actin-myosin interactions by inhibiting ATPase activity in a calcium-calmodulin sensitive manner.^[3]

Mutations in nebulin cause some cases of the autosomal recessive disorder nemaline myopathy.^[4]

A second smaller isoform of nebulin, termed nebulette, is expressed in cardiac muscle.

Structure

The structure of the SH3 domain of nebulin was determined by NMR.^[1] The SH3 domain from nebulin is composed of 60 amino acid residues, of which 30 percent is in the beta sheet secondary struture (7 strands; 18 residues).

Knockout phenotype

As of 2007, two knockout mouse models for nebulin have been developed to better understand its in vivo function. Bang and colleagues^[5] demonstrated that nebulin-knockout mice die postnatally, have reduced thin filament length, and impaired contractile function. Postnatal sarcomere disorganization and degeneration occurred rapidly in these mice, indicating the nebulin is essential for maintaining the structural integrity of myofibrils. Witt and colleagues^[6] had similar results in their mice, which also died postnatally with reduced thin filament length and contractile function. These nebulin-knockout mice are being investigated as animal models of nemaline myopathy.

References

1. ^ ^{a b} 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. ^ McElhinny et al. (2003). "Nebulin: the nebulous, multifunctional giant of striated muscle". Trends Cardiovasc Med 13 (5): 195–201. doi:10.1016/S1050-1738(03)00076-8. PMID 12837582. 
3. ^ Root & Wang; Wang, K (1994). "Calmodulin-sensitive interaction of human nebulin fragments with actin and myosin". Biochemistry 33 (42): 12581–91. doi:10.1021/bi00208a008. PMID 7918483. 
4. ^ Pelin et al. (1999). "Mutations in the nebulin gene associated with autosomal recessive nemaline myopathy". Proc Natl Acad Sci USA 96 (5): 2305–10. doi:10.1073/pnas.96.5.2305. PMC 26779. PMID 10051637. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=26779. 
5. ^ Bang et al. (2006). "Nebulin-deficient mice exhibit shorter thin filament lengths and reduced contractile function in skeletal muscle". J Cell Biol 173 (6): 905–16. doi:10.1083/jcb.200603119. PMC 2063916. PMID 16769824. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2063916. 
6. ^ Witt et al. (2006). "Nebulin regulates thin filament length, contractility, and Z-disk structure in vivo". EMBO J 25 (16): 3843–55. doi:10.1038/sj.emboj.7601242. PMC 1553189. PMID 16902413. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1553189. 

External links

• MeSH nebulin
• GeneReviews/NCBI/NIH/UW entry on Nemaline Myopathy