NRAP

{{Short description|Protein-coding gene in the species Homo sapiens}}

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.{{cite journal | vauthors = Mohiddin SA, Lu S, Cardoso JP, Carroll S, Jha S, Horowits R, Fananapazir L | title = Genomic organization, alternative splicing, and expression of human and mouse N-RAP, a nebulin-related LIM protein of striated muscle | journal = Cell Motility and the Cytoskeleton | volume = 55 | issue = 3 | pages = 200–212 | date = July 2003 | pmid = 12789664 | doi = 10.1002/cm.10123 }}{{cite journal | vauthors = Luo G, Herrera AH, Horowits R | title = Molecular interactions of N-RAP, a nebulin-related protein of striated muscle myotendon junctions and intercalated disks | journal = Biochemistry | volume = 38 | issue = 19 | pages = 6135–43 | date = May 1999 | pmid = 10320340 | doi = 10.1021/bi982395t }}{{cite web | title = Entrez Gene: NRAP nebulin-related anchoring protein| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4892}}{{cite journal | vauthors = Pappas CT, Bliss KT, Zieseniss A, Gregorio CC | title = The Nebulin family: an actin support group | journal = Trends in Cell Biology | volume = 21 | issue = 1 | pages = 29–37 | date = January 2011 | pmid = 20951588 | pmc = 3014390 | doi = 10.1016/j.tcb.2010.09.005 }}

Structure

N-RAP is a 197 kDa protein composed of 1730 amino acids.{{cite web | url = http://www.heartproteome.org/copa/ProteinInfo.aspx?QType=Protein%20ID&QValue=Q86VF7 | work = Cardiac Organellar Protein Atlas Knowledgebase (COPaKB) | title = Nebulin-related-anchoring protein }}{{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 | pages = 1043–1053 | date = October 2013 | pmid = 23965338 | pmc = 4076475 | doi = 10.1161/CIRCRESAHA.113.301151 }} 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 DxxY K motif.{{cite journal | vauthors = Labeit S, Gibson T, Lakey A, Leonard K, Zeviani M, Knight P, Wardale J, Trinick J | title = Evidence that nebulin is a protein-ruler in muscle thin filaments | journal = FEBS Letters | volume = 282 | issue = 2 | pages = 313–316 | date = May 1991 | pmid = 2037050 | doi = 10.1016/0014-5793(91)80503-u | doi-access = free | bibcode = 1991FEBSL.282..313L }} 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.{{cite journal | vauthors = Labeit S, Kolmerer B | title = The complete primary structure of human nebulin and its correlation to muscle structure | journal = Journal of Molecular Biology | volume = 248 | issue = 2 | pages = 308–315 | date = April 1995 | pmid = 7739042 | doi = 10.1016/s0022-2836(95)80052-2 }} 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.

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.{{cite journal | vauthors = Dhume A, Lu S, Horowits R | title = Targeted disruption of N-RAP gene function by RNA interference: a role for N-RAP in myofibril organization | journal = Cell Motility and the Cytoskeleton | volume = 63 | issue = 8 | pages = 493–511 | date = August 2006 | pmid = 16767749 | doi = 10.1002/cm.20141 }} 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,{{cite journal | vauthors = Carroll S, Lu S, Herrera AH, Horowits R | title = N-RAP scaffolds I-Z-I assembly during myofibrillogenesis in cultured chick cardiomyocytes | journal = Journal of Cell Science | volume = 117 | issue = Pt 1 | pages = 105–114 | date = January 2004 | pmid = 14657273 | doi = 10.1242/jcs.00847 | doi-access = free }} and dynamic imaging studies have shown that N-RAP departs from the I-Z-I complexes upon completion of actin thin filament assembly.{{cite journal | vauthors = Manisastry SM, Zaal KJ, Horowits R | title = Myofibril assembly visualized by imaging N-RAP, alpha-actinin, and actin in living cardiomyocytes | journal = Experimental Cell Research | volume = 315 | issue = 12 | pages = 2126–2139 | date = July 2009 | pmid = 19233165 | pmc = 2742992 | doi = 10.1016/j.yexcr.2009.02.006 }} In adult cardiac muscle, N-RAP colocalizes to intercalated discs,{{cite journal | vauthors = Lu S, Borst DE, Horowits R | title = N-RAP expression during mouse heart development | journal = Developmental Dynamics | volume = 233 | issue = 1 | pages = 201–212 | date = May 2005 | pmid = 15765519 | doi = 10.1002/dvdy.20314 | s2cid = 22925166 | doi-access = free }} 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.{{cite journal | vauthors = Luo G, Zhang JQ, Nguyen TP, Herrera AH, Paterson B, Horowits R | title = Complete cDNA sequence and tissue localization of N-RAP, a novel nebulin-related protein of striated muscle | journal = Cell Motility and the Cytoskeleton | volume = 38 | issue = 1 | pages = 75–90 | year = 1997 | pmid = 9295142 | doi = 10.1002/(SICI)1097-0169(1997)38:1<75::AID-CM7>3.0.CO;2-G }}

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.{{cite journal | vauthors = Sussman MA, Welch S, Cambon N, Klevitsky R, Hewett TE, Price R, Witt SA, Kimball TR | title = Myofibril degeneration caused by tropomodulin overexpression leads to dilated cardiomyopathy in juvenile mice | journal = The Journal of Clinical Investigation | volume = 101 | issue = 1 | pages = 51–61 | date = January 1998 | pmid = 9421465 | pmc = 508539 | doi = 10.1172/JCI1167 }}{{cite journal | vauthors = Ehler E, Horowits R, Zuppinger C, Price RL, Perriard E, Leu M, Caroni P, Sussman M, Eppenberger HM, Perriard JC | title = Alterations at the intercalated disk associated with the absence of muscle LIM protein | journal = The Journal of Cell Biology | volume = 153 | issue = 4 | pages = 763–772 | date = May 2001 | pmid = 11352937 | pmc = 2192386 | doi = 10.1083/jcb.153.4.763 }} 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.

NRAP

Structure

Function

Clinical significance

References

Further reading