Nebulin-related-anchoring protein(N-RAP) is a protein that in humans is encoded by the NRAPgene. N-RAP is a muscle-specific isoform belonging to the nebulin family of proteins. This family is composed of 5 members: N-RAP, nebulin, nebulette, LASP-1 and LASP-2. N-RAP is involved in both myofibrillar myogenesis during development and cell-cell connections in mature muscle.[1][2][3][4]
N-RAP is a 197 kDa protein composed of 1730 amino acids.[5][6] 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.[7] Like 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.[8] A unique feature of NRAP relative to nebulin is its N-terminal cysteine-rich LIM domain, a feature shared with LASP-1 and LASP-2.[4]
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.[9] Specifically, studies suggest that NRAP super repeats may be an essential scaffold for organizing alpha-actinin and actin into sarcomereicI-Z-I complexes in premyofibrils,[10] and dynamic imaging studies have shown that N-RAP departs from the I-Z-I complexes upon completion of actin thin filament assembly.[11] In adult cardiac muscle, N-RAP colocalizes to intercalated discs,[12] where it functions to anchor terminal actin filaments to the sarcolemma. It has been suggested that its role in adult muscle is force transduction from the sarcomere to the extracellular matrix.[13]
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.[14][15] This has been hypothesized to be an adaptive response to correct for disorganized actin thin filament architecture at intercalated disc junctions in cardiomyocytes during dilated cardiomyopathy.
References
↑Mohiddin SA, Lu S, Cardoso JP, Carroll S, Jha S, Horowits R, Fananapazir L (Jul 2003). "Genomic organization, alternative splicing, and expression of human and mouse N-RAP, a nebulin-related LIM protein of striated muscle". Cell Motility and the Cytoskeleton. 55 (3): 200–12. doi:10.1002/cm.10123. PMID12789664.
↑Luo G, Herrera AH, Horowits R (May 1999). "Molecular interactions of N-RAP, a nebulin-related protein of striated muscle myotendon junctions and intercalated disks". Biochemistry. 38 (19): 6135–43. doi:10.1021/bi982395t. PMID10320340.
↑Labeit S, Gibson T, Lakey A, Leonard K, Zeviani M, Knight P, Wardale J, Trinick J (May 1991). "Evidence that nebulin is a protein-ruler in muscle thin filaments". FEBS Letters. 282 (2): 313–6. doi:10.1016/0014-5793(91)80503-u. PMID2037050.
↑Labeit S, Kolmerer B (Apr 1995). "The complete primary structure of human nebulin and its correlation to muscle structure". Journal of Molecular Biology. 248 (2): 308–15. doi:10.1016/s0022-2836(95)80052-2. PMID7739042.
↑Dhume A, Lu S, Horowits R (Aug 2006). "Targeted disruption of N-RAP gene function by RNA interference: a role for N-RAP in myofibril organization". Cell Motility and the Cytoskeleton. 63 (8): 493–511. doi:10.1002/cm.20141. PMID16767749.
↑Carroll S, Lu S, Herrera AH, Horowits R (Jan 2004). "N-RAP scaffolds I-Z-I assembly during myofibrillogenesis in cultured chick cardiomyocytes". Journal of Cell Science. 117 (Pt 1): 105–14. doi:10.1242/jcs.00847. PMID14657273.
↑Lu S, Borst DE, Horowits R (May 2005). "N-RAP expression during mouse heart development". Developmental Dynamics. 233 (1): 201–12. doi:10.1002/dvdy.20314. PMID15765519.
↑Luo G, Zhang JQ, Nguyen TP, Herrera AH, Paterson B, Horowits R (1997). "Complete cDNA sequence and tissue localization of N-RAP, a novel nebulin-related protein of striated muscle". Cell Motility and the Cytoskeleton. 38 (1): 75–90. doi:10.1002/(SICI)1097-0169(1997)38:1<75::AID-CM7>3.0.CO;2-G. PMID9295142.
Lanfranchi G, Muraro T, Caldara F, Pacchioni B, Pallavicini A, Pandolfo D, Toppo S, Trevisan S, Scarso S, Valle G (Jan 1996). "Identification of 4370 expressed sequence tags from a 3'-end-specific cDNA library of human skeletal muscle by DNA sequencing and filter hybridization". Genome Research. 6 (1): 35–42. doi:10.1101/gr.6.1.35. PMID8681137.
Luo G, Zhang JQ, Nguyen TP, Herrera AH, Paterson B, Horowits R (1997). "Complete cDNA sequence and tissue localization of N-RAP, a novel nebulin-related protein of striated muscle". Cell Motility and the Cytoskeleton. 38 (1): 75–90. doi:10.1002/(SICI)1097-0169(1997)38:1<75::AID-CM7>3.0.CO;2-G. PMID9295142.
Luo G, Leroy E, Kozak CA, Polymeropoulos MH, Horowits R (Oct 1997). "Mapping of the gene (NRAP) encoding N-RAP in the mouse and human genomes". Genomics. 45 (1): 229–32. doi:10.1006/geno.1997.4917. PMID9339382.
Witt SH, Granzier H, Witt CC, Labeit S (Jul 2005). "MURF-1 and MURF-2 target a specific subset of myofibrillar proteins redundantly: towards understanding MURF-dependent muscle ubiquitination". Journal of Molecular Biology. 350 (4): 713–22. doi:10.1016/j.jmb.2005.05.021. PMID15967462.
Mehrle A, Rosenfelder H, Schupp I, del Val C, Arlt D, Hahne F, Bechtel S, Simpson J, Hofmann O, Hide W, Glatting KH, Huber W, Pepperkok R, Poustka A, Wiemann S (Jan 2006). "The LIFEdb database in 2006". Nucleic Acids Research. 34 (Database issue): D415–8. doi:10.1093/nar/gkj139. PMC1347501. PMID16381901.