NRAP

Nebulin-related-anchoring protein (N-RAP) is a protein that in humans is encoded by the NRAP gene. 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.[5][6][7][8]

NRAP
Identifiers
AliasesNRAP, N-RAP, nebulin related anchoring protein
External IDsOMIM: 602873 MGI: 1098765 HomoloGene: 4499 GeneCards: NRAP
Orthologs
SpeciesHumanMouse
Entrez

4892

18175

Ensembl

ENSG00000197893

ENSMUSG00000049134

UniProt

Q86VF7

Q80XB4

RefSeq (mRNA)

NM_001261463
NM_006175
NM_198060
NM_001322945

NM_001286552
NM_008733
NM_198059

RefSeq (protein)

NP_001248392
NP_001309874
NP_006166
NP_932326

Location (UCSC)Chr 10: 113.59 – 113.66 MbChr 19: 56.31 – 56.38 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Structure

N-RAP is a 197 kDa protein composed of 1730 amino acids.[9][10] 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.[11] 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.[12] 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.[8]

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.[13] Specifically, studies suggest that NRAP super repeats may be an essential scaffold for organizing alpha-actinin and actin into sarcomereic I-Z-I complexes in premyofibrils,[14] and dynamic imaging studies have shown that N-RAP departs from the I-Z-I complexes upon completion of actin thin filament assembly.[15] In adult cardiac muscle, N-RAP colocalizes to intercalated discs,[16] 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.[17]

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.[18][19] 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
  1. GRCh38: Ensembl release 89: ENSG00000197893 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000049134 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 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. PMID 12789664.
  6. 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. PMID 10320340.
  7. "Entrez Gene: NRAP nebulin-related anchoring protein".
  8. Pappas CT, Bliss KT, Zieseniss A, Gregorio CC (Jan 2011). "The Nebulin family: an actin support group". Trends in Cell Biology. 21 (1): 29–37. doi:10.1016/j.tcb.2010.09.005. PMC 3014390. PMID 20951588.
  9. "Nebulin-related-anchoring protein". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB).
  10. Zong, N. C.; Li, H; Li, H; Lam, M. P.; Jimenez, R. C.; Kim, C. S.; Deng, N; Kim, A. K.; Choi, J. H.; Zelaya, I; Liem, D; Meyer, D; Odeberg, J; Fang, C; Lu, H. J.; Xu, T; Weiss, J; Duan, H; Uhlen, M; Yates Jr, 3rd; Apweiler, R; Ge, J; Hermjakob, H; Ping, P (2013). "Integration of cardiac proteome biology and medicine by a specialized knowledgebase". Circulation Research. 113 (9): 1043–53. doi:10.1161/CIRCRESAHA.113.301151. PMC 4076475. PMID 23965338.
  11. 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. PMID 2037050.
  12. 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. PMID 7739042.
  13. 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. PMID 16767749.
  14. 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. PMID 14657273.
  15. Manisastry SM, Zaal KJ, Horowits R (Jul 2009). "Myofibril assembly visualized by imaging N-RAP, alpha-actinin, and actin in living cardiomyocytes". Experimental Cell Research. 315 (12): 2126–39. doi:10.1016/j.yexcr.2009.02.006. PMC 2742992. PMID 19233165.
  16. 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. PMID 15765519. S2CID 22925166.
  17. 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. PMID 9295142.
  18. Sussman MA, Welch S, Cambon N, Klevitsky R, Hewett TE, Price R, Witt SA, Kimball TR (Jan 1998). "Myofibril degeneration caused by tropomodulin overexpression leads to dilated cardiomyopathy in juvenile mice". The Journal of Clinical Investigation. 101 (1): 51–61. doi:10.1172/JCI1167. PMC 508539. PMID 9421465.
  19. Ehler E, Horowits R, Zuppinger C, Price RL, Perriard E, Leu M, Caroni P, Sussman M, Eppenberger HM, Perriard JC (May 2001). "Alterations at the intercalated disk associated with the absence of muscle LIM protein". The Journal of Cell Biology. 153 (4): 763–72. doi:10.1083/jcb.153.4.763. PMC 2192386. PMID 11352937.

Further reading
  1. 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 (Oct 2013). "Integration of cardiac proteome biology and medicine by a specialized knowledgebase". Circulation Research. 113 (9): 1043–1053. doi:10.1161/CIRCRESAHA.113.301151. PMC 4076475. PMID 23965338.
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