NRAP

Last updated
NRAP
Identifiers
Aliases NRAP , N-RAP, nebulin related anchoring protein
External IDs OMIM: 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 Mb Chr 19: 56.31 – 56.38 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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]

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 S Dxx Y K motif. [11] 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. [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.

Related Research Articles

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<span class="mw-page-title-main">MYH7</span>

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<span class="mw-page-title-main">Nebulin</span>

Nebulin is an actin-binding protein which is localized to the thin filament of the sarcomeres in skeletal muscle. Nebulin in humans is coded for by the gene NEB. It is a very large protein and binds as many as 200 actin monomers. Because its length is proportional to thin filament length, it is believed that nebulin acts as a thin filament "ruler" and regulates thin filament length during sarcomere assembly and acts as the coats the actin filament. Other functions of nebulin, such as a role in cell signaling, remain uncertain.

<span class="mw-page-title-main">Paxillin</span>

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<span class="mw-page-title-main">Nebulette</span> Protein-coding gene in the species Homo sapiens

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 cardiac muscle and appears to regulate the length of actin thin filaments.

<span class="mw-page-title-main">Cadherin-2</span>

Cadherin-2 also known as Neural cadherin (N-cadherin), is a protein that in humans is encoded by the CDH2 gene. CDH2 has also been designated as CD325 . Cadherin-2 is a transmembrane protein expressed in multiple tissues and functions to mediate cell–cell adhesion. In cardiac muscle, Cadherin-2 is an integral component in adherens junctions residing at intercalated discs, which function to mechanically and electrically couple adjacent cardiomyocytes. Alterations in expression and integrity of Cadherin-2 has been observed in various forms of disease, including human dilated cardiomyopathy. Variants in CDH2 have also been identified to cause a syndromic neurodevelopmental disorder.

<span class="mw-page-title-main">TPM1</span>

Tropomyosin alpha-1 chain is a protein that in humans is encoded by the TPM1 gene. This gene is a member of the tropomyosin (Tm) family of highly conserved, widely distributed actin-binding proteins involved in the contractile system of striated and smooth muscles and the cytoskeleton of non-muscle cells.

<span class="mw-page-title-main">Alpha-actinin-2</span> Protein-coding gene in the species Homo sapiens

Alpha-actinin-2 is a protein which in humans is encoded by the ACTN2 gene. This gene encodes an alpha-actinin isoform that is expressed in both skeletal and cardiac muscles and functions to anchor myofibrillar actin thin filaments and titin to Z-discs.

<span class="mw-page-title-main">Myosin binding protein C, cardiac</span>

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<span class="mw-page-title-main">FLNC (gene)</span>

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<span class="mw-page-title-main">Telethonin</span>

Telethonin, also known as Tcap, is a protein that in humans is encoded by the TCAP gene. Telethonin is expressed in cardiac and skeletal muscle at Z-discs and functions to regulate sarcomere assembly, T-tubule function and apoptosis. Telethonin has been implicated in several diseases, including limb-girdle muscular dystrophy, hypertrophic cardiomyopathy, dilated cardiomyopathy and idiopathic cardiomyopathy.

<span class="mw-page-title-main">MYH10</span> Protein-coding gene in the species Homo sapiens

Myosin-10 also known as myosin heavy chain 10 or non-muscle myosin IIB (NM-IIB) is a protein that in humans is encoded by the MYH10 gene. Non-muscle myosins are expressed in a wide variety of tissues, but NM-IIB is the only non-muscle myosin II isoform expressed in cardiac muscle, where it localizes to adherens junctions within intercalated discs. NM-IIB is essential for normal development of cardiac muscle and for integrity of intercalated discs. Mutations in MYH10 have been identified in patients with left atrial enlargement.

<span class="mw-page-title-main">MYOT</span> Mammalian protein found in Homo sapiens

Myotilin is a protein that in humans is encoded by the MYOT gene. Myotilin also known as TTID is a muscle protein that is found within the Z-disc of sarcomeres.

<span class="mw-page-title-main">Plakophilin-2</span>

Plakophilin-2 is a protein that in humans is encoded by the PKP2 gene. Plakophilin 2 is expressed in skin and cardiac muscle, where it functions to link cadherins to intermediate filaments in the cytoskeleton. In cardiac muscle, plakophilin-2 is found in desmosome structures located within intercalated discs. Mutations in PKP2 have been shown to be causal in arrhythmogenic right ventricular cardiomyopathy.

<span class="mw-page-title-main">Obscurin</span>

Obscurin is a protein that in humans is encoded by the OBSCN gene. Obscurin belongs to the family of giant sarcomeric signaling proteins that includes titin and nebulin. Obscurin is expressed in cardiac and skeletal muscle, and plays a role in the organization of myofibrils during sarcomere assembly. A mutation in the OBSCN gene has been associated with hypertrophic cardiomyopathy and altered obscurin protein properties have been associated with other muscle diseases.

<span class="mw-page-title-main">ANKRD1</span> Protein-coding gene in the species Homo sapiens

Ankyrin repeat domain-containing protein 1, or Cardiac ankyrin repeat protein is a protein that in humans is encoded by the ANKRD1 gene also known as CARP. CARP is highly expressed in cardiac and skeletal muscle, and is a transcription factor involved in development and under conditions of stress. CARP has been implicated in several diseases, including dilated cardiomyopathy, hypertrophic cardiomyopathy, and several skeletal muscle myopathies.

<span class="mw-page-title-main">CSRP3</span>

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<span class="mw-page-title-main">Myopalladin</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">Catenin alpha-1</span> Protein-coding gene in the species Homo sapiens

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References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000197893 - Ensembl, May 2017
  2. 1 2 3 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. 1 2 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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