Nebulin-related-anchoring protein (N-RAP) is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

that in humans is encoded by the ''NRAP''

gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

. N-RAP is a muscle-specific

isoform A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some iso ...

belonging to the nebulin family of

s. This family is composed of 5 members: N-RAP, nebulin,

nebulette Nebulette is a cardiac-specific isoform belonging to the nebulin family of proteins. It is encoded by the ''NEBL'' gene. This family is composed of 5 members: nebulette, nebulin, N-RAP, LASP-1 and LASP-2. Nebulette localizes to Z-discs of cardi ...

, 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 S Dxx Y K motif. Like nebulin, groups of seven single repeats within N-RAP form “super repeats”, which incorporate a single conserved motif W L K G I G W at the end of the third repeat. A unique feature of NRAP relative to nebulin is its N-terminal cysteine-rich

LIM domain LIM domains are protein structural domains, composed of two contiguous zinc fingers, separated by a two-amino acid residue hydrophobic linker. The domain name is an acronym of the three genes in which it was first identified (LIN-11, Isl-1 and ...

, 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 Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of ov ...

into

sarcomere A sarcomere (Greek σάρξ ''sarx'' "flesh", μέρος ''meros'' "part") is the smallest functional unit of striated muscle tissue. It is the repeating unit between two Z-lines. Skeletal muscles are composed of tubular muscle cells (called mus ...

ic 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

intercalated discs Intercalated discs or lines of Eberth are microscopic identifying features of cardiac muscle. Cardiac muscle consists of individual heart muscle cells (cardiomyocytes) connected by intercalated discs to work as a single functional syncytium. By con ...

, where it functions to anchor terminal

filaments to the

sarcolemma The sarcolemma (''sarco'' (from ''sarx'') from Greek; flesh, and ''lemma'' from Greek; sheath) also called the myolemma, is the cell membrane surrounding a skeletal muscle fiber or a cardiomyocyte. It consists of a lipid bilayer and a thin oute ...

. 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

dilated cardiomyopathy Dilated cardiomyopathy (DCM) is a condition in which the heart becomes enlarged and cannot pump blood effectively. Symptoms vary from none to feeling tired, leg swelling, and shortness of breath. It may also result in chest pain or fainting. Co ...

. This has been hypothesized to be an adaptive response to correct for disorganized actin thin filament architecture at

intercalated disc Intercalated discs or lines of Eberth are microscopic identifying features of cardiac muscle. Cardiac muscle consists of individual heart muscle cells (cardiomyocytes) connected by intercalated discs to work as a single functional syncytium. By con ...

junctions in cardiomyocytes during

References

External links

* .{{cite 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 , pmc=4076475 , pages=1043–1053

Structure

Function

Clinical significance

References

Further reading

External links