NRAP

Nebulin-related-anchoring protein (N-RAP) is a is_associated_with::protein that in humans is encoded by the NRAP is_associated_with::gene. N-RAP is a muscle-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: N-RAP, is_associated_with::nebulin, is_associated_with::nebulette, LASP-1 and LASP-2. N-RAP is involved in both myofibrillar myogenesis during development and cell-cell connections in mature muscle.

Structure
N-RAP is a 197 kDa protein composed of 1730 amino acids. As a member of the nebulin family of proteins, N-RAP is characterized by 35 amino acid stretches of ‘‘nebulin repeats’’, which are actin binding domains containing a conserved SDxxYK motif. Like is_associated_with::nebulin, groups of seven single repeats within N-RAP form “super repeats”, which incorporate a single conserved motif WLKGIGW at the end of the third repeat. A unique feature of NRAP relative to is_associated_with::nebulin is its N-terminal is_associated_with::cysteine-rich is_associated_with::LIM domain, a feature shared with LASP-1 and LASP-2.

Function
An important role has been implicated for N-RAP in myofibrilar organization during cardiomyocyte development. It is clear that NRAP is critical for normal α-actinin-dependent organization of myofibrils in cardiomyocytes, as knock-down of N-RAP protein levels causes myofbrillar disassembly in embryonic cardiomyocytes. Specifically, studies suggest that NRAP super repeats may be an essential scaffold for organizing alpha-actinin and actin into is_associated_with::sarcomereic I-Z-I complexes in premyofibrils, and dynamic imaging studies have shown that N-RAP departs from the I-Z-I complexes upon completion of actin thin filament assembly. In adult cardiac muscle, N-RAP colocalizes to is_associated_with::intercalated discs, where it functions to anchor terminal actin filaments to the is_associated_with::sarcolemma. It has been suggested that its role in adult muscle is force transduction from the sarcomere to the extracellular matrix.

Clinical significance
Though no known direct link exists between N-RAP mutations and human cardiomyopathies, N-RAP has been shown to be significantly upregulated in murine models of is_associated_with::dilated cardiomyopathy. This has been hypothesized to be an adaptive response to correct for disorganized actin thin filament architecture at is_associated_with::intercalated disc junctions in cardiomyocytes during is_associated_with::dilated cardiomyopathy.