Nebulette

The NEBL is_associated_with::gene encodes the is_associated_with::protein Nebulette, a is_associated_with::cardiac-specific is_associated_with::isoform belonging to the is_associated_with::nebulin family of is_associated_with::proteins. This family is composed of 5 members: nebulette, is_associated_with::nebulin, N-RAP, LASP-1 and LASP-2. Nebulette localizes to Z-discs of is_associated_with::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. 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. 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. Though nebulette shares structural features with nebulin, nebulin is expressed preferentially in is_associated_with::skeletal muscle and has an enormous size (600-900 kDa), while nebulette is expressed in is_associated_with::cardiac muscle at Z-disc regions and is significantly smaller (roughly 1/6 of the size). Nebulette interacts with actin, tropomyosin, alpha-actinin. Xin, and is_associated_with::XIRP2.

Function
Nebulette was identified in 1995 by Moncman and Wang using primary cultures of chicken embryonic is_associated_with::cardiomyocytes by is_associated_with::immunoprecipitations with certain anti-nebulin is_associated_with::monoclonal antibodies. Normal expression of nebulette is essential for the assembly and contractile function of is_associated_with::myofibrils. 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.

Clinical significance
Mutations in the NEBL gene have been associated with is_associated_with::dilated cardiomyopathy. Studies in transgenic mice have supported their causative role in endocardial fibroelastosis and is_associated_with::dilated cardiomyopathy.