NRAP

Nebulin-related anchoring protein
Identifiers
Symbols	NRAP ; N-RAP
External IDs	OMIM: 602873 MGI: 1098765 HomoloGene: 4499 GeneCards: NRAP Gene
Gene ontology Molecular function • actin binding • zinc ion binding • muscle alpha-actinin binding Cellular component • fascia adherens • muscle tendon junction Biological process • biological_process Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	4892	18175
Ensembl	ENSG00000197893	ENSMUSG00000049134
UniProt	Q86VF7	Q80XB4
RefSeq (mRNA)	NM_001261463	NM_001286552
RefSeq (protein)	NP_001248392	NP_001273481
Location (UCSC)	Chr 10: 113.59 – 113.66 Mb	Chr 19: 56.32 – 56.39 Mb
PubMed search

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.^[1][2][3][4]

Structure

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 sarcomereic I-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

1. 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.
2. 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.
3. "Entrez Gene: NRAP nebulin-related anchoring protein".
4. 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. PMID 20951588.
5. "Nebulin-related-anchoring protein". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB).
6. 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.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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. PMID 19233165.
12. 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.
13. 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.
14. 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. PMID 9421465.
15. 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. PMID 11352937.

Further reading

• 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. PMID 8681137.
• 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.
• 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. PMID 9339382.
• Hartley JL, Temple GF, Brasch MA (Nov 2000). "DNA cloning using in vitro site-specific recombination". Genome Research 10 (11): 1788–95. doi:10.1101/gr.143000. PMC 310948. PMID 11076863.
• Wiemann S, Weil B, Wellenreuther R, Gassenhuber J, Glassl S, Ansorge W, Böcher M, Blöcker H, Bauersachs S, Blum H, Lauber J, Düsterhöft A, Beyer A, Köhrer K, Strack N, Mewes HW, Ottenwälder B, Obermaier B, Tampe J, Heubner D, Wambutt R, Korn B, Klein M, Poustka A (Mar 2001). "Toward a catalog of human genes and proteins: sequencing and analysis of 500 novel complete protein coding human cDNAs". Genome Research 11 (3): 422–35. doi:10.1101/gr.GR1547R. PMC 311072. PMID 11230166.
• Wiemann S, Arlt D, Huber W, Wellenreuther R, Schleeger S, Mehrle A, Bechtel S, Sauermann M, Korf U, Pepperkok R, Sültmann H, Poustka A (Oct 2004). "From ORFeome to biology: a functional genomics pipeline". Genome Research 14 (10B): 2136–44. doi:10.1101/gr.2576704. PMC 528930. PMID 15489336.
• 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. PMID 15967462.
• 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. PMC 1347501. PMID 16381901.

External links

• "Mass spectrometry characterization of human NRAP". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB)..^[1]

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.