| Structural highlights
Disease
[XRP2_HUMAN] Defects in RP2 are the cause of retinitis pigmentosa type 2 (RP2) [MIM:312600]; also known as X-linked retinitis pigmentosa 2 (XLRP-2). RP leads to degeneration of retinal photoreceptor cells. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13]
Function
[XRP2_HUMAN] Acts as a GTPase-activating protein (GAP) involved in trafficking between the Golgi and the ciliary membrane. Involved in localization of proteins, such as NPHP3, to the cilium membrane by inducing hydrolysis of GTP ARL3, leading to the release of UNC119 (or UNC119B). Acts as a GTPase-activating protein (GAP) for tubulin in concert with tubulin-specific chaperone C, but does not enhance tubulin heterodimerization. Acts as guanine nucleotide dissociation inhibitor towards ADP-ribosylation factor-like proteins.[14] [15] [16] [17]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
The crystal structure of human retinitis pigmentosa 2 protein (RP2) was solved to 2.1 angstroms resolution. It consists of an N-terminal beta helix and a C-terminal ferredoxin-like alpha/beta domain. RP2 is functionally and structurally related to the tubulin-specific chaperone cofactor C. Seven of nine known RP2 missense mutations identified in patients are located in the beta helix domain, and most of them cluster to the hydrophobic core and are likely to destabilize the protein. Two residues, Glu138 and the catalytically important Arg118, are solvent-exposed and form a salt bridge, indicating that Glu138 might be critical for positioning Arg118 for catalysis. RP2 is a specific effector protein of Arl3. The N-terminal 34 residues and beta helix domain of RP2 are required for this interaction. The abilitities of RP2 to bind Arl3 and cause retinitis pigmentosa seem to be correlated, since both the R118H and E138G mutants show a drastically reduced affinity to Arl3.
Crystal structure of the human retinitis pigmentosa 2 protein and its interaction with Arl3.,Kuhnel K, Veltel S, Schlichting I, Wittinghofer A Structure. 2006 Feb;14(2):367-78. PMID:16472755[18]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Bartolini F, Bhamidipati A, Thomas S, Schwahn U, Lewis SA, Cowan NJ. Functional overlap between retinitis pigmentosa 2 protein and the tubulin-specific chaperone cofactor C. J Biol Chem. 2002 Apr 26;277(17):14629-34. Epub 2002 Feb 14. PMID:11847227 doi:10.1074/jbc.M200128200
- ↑ Kuhnel K, Veltel S, Schlichting I, Wittinghofer A. Crystal structure of the human retinitis pigmentosa 2 protein and its interaction with Arl3. Structure. 2006 Feb;14(2):367-78. PMID:16472755 doi:10.1016/j.str.2005.11.008
- ↑ Chapple JP, Hardcastle AJ, Grayson C, Spackman LA, Willison KR, Cheetham ME. Mutations in the N-terminus of the X-linked retinitis pigmentosa protein RP2 interfere with the normal targeting of the protein to the plasma membrane. Hum Mol Genet. 2000 Aug 12;9(13):1919-26. PMID:10942419
- ↑ Schwahn U, Lenzner S, Dong J, Feil S, Hinzmann B, van Duijnhoven G, Kirschner R, Hemberger M, Bergen AA, Rosenberg T, Pinckers AJ, Fundele R, Rosenthal A, Cremers FP, Ropers HH, Berger W. Positional cloning of the gene for X-linked retinitis pigmentosa 2. Nat Genet. 1998 Aug;19(4):327-32. PMID:9697692 doi:10.1038/1214
- ↑ Hardcastle AJ, Thiselton DL, Van Maldergem L, Saha BK, Jay M, Plant C, Taylor R, Bird AC, Bhattacharya S. Mutations in the RP2 gene cause disease in 10% of families with familial X-linked retinitis pigmentosa assessed in this study. Am J Hum Genet. 1999 Apr;64(4):1210-5. PMID:10090907
- ↑ Rosenberg T, Schwahn U, Feil S, Berger W. Genotype-phenotype correlation in X-linked retinitis pigmentosa 2 (RP2). Ophthalmic Genet. 1999 Sep;20(3):161-72. PMID:10520237
- ↑ Wada Y, Nakazawa M, Abe T, Tamai M. A new Leu253Arg mutation in the RP2 gene in a Japanese family with X-linked retinitis pigmentosa. Invest Ophthalmol Vis Sci. 2000 Jan;41(1):290-3. PMID:10634633
- ↑ Sharon D, Bruns GA, McGee TL, Sandberg MA, Berson EL, Dryja TP. X-linked retinitis pigmentosa: mutation spectrum of the RPGR and RP2 genes and correlation with visual function. Invest Ophthalmol Vis Sci. 2000 Aug;41(9):2712-21. PMID:10937588
- ↑ Miano MG, Testa F, Filippini F, Trujillo M, Conte I, Lanzara C, Millan JM, De Bernardo C, Grammatico B, Mangino M, Torrente I, Carrozzo R, Simonelli F, Rinaldi E, Ventruto V, D'Urso M, Ayuso C, Ciccodicola A. Identification of novel RP2 mutations in a subset of X-linked retinitis pigmentosa families and prediction of new domains. Hum Mutat. 2001 Aug;18(2):109-19. PMID:11462235 doi:10.1002/humu.1160
- ↑ Breuer DK, Yashar BM, Filippova E, Hiriyanna S, Lyons RH, Mears AJ, Asaye B, Acar C, Vervoort R, Wright AF, Musarella MA, Wheeler P, MacDonald I, Iannaccone A, Birch D, Hoffman DR, Fishman GA, Heckenlively JR, Jacobson SG, Sieving PA, Swaroop A. A comprehensive mutation analysis of RP2 and RPGR in a North American cohort of families with X-linked retinitis pigmentosa. Am J Hum Genet. 2002 Jun;70(6):1545-54. Epub 2002 Apr 30. PMID:11992260 doi:10.1086/340848
- ↑ Sharon D, Sandberg MA, Rabe VW, Stillberger M, Dryja TP, Berson EL. RP2 and RPGR mutations and clinical correlations in patients with X-linked retinitis pigmentosa. Am J Hum Genet. 2003 Nov;73(5):1131-46. Epub 2003 Oct 16. PMID:14564670 doi:S0002-9297(07)61975-2
- ↑ Bader I, Brandau O, Achatz H, Apfelstedt-Sylla E, Hergersberg M, Lorenz B, Wissinger B, Wittwer B, Rudolph G, Meindl A, Meitinger T. X-linked retinitis pigmentosa: RPGR mutations in most families with definite X linkage and clustering of mutations in a short sequence stretch of exon ORF15. Invest Ophthalmol Vis Sci. 2003 Apr;44(4):1458-63. PMID:12657579
- ↑ Neveling K, Collin RW, Gilissen C, van Huet RA, Visser L, Kwint MP, Gijsen SJ, Zonneveld MN, Wieskamp N, de Ligt J, Siemiatkowska AM, Hoefsloot LH, Buckley MF, Kellner U, Branham KE, den Hollander AI, Hoischen A, Hoyng C, Klevering BJ, van den Born LI, Veltman JA, Cremers FP, Scheffer H. Next-generation genetic testing for retinitis pigmentosa. Hum Mutat. 2012 Jun;33(6):963-72. doi: 10.1002/humu.22045. Epub 2012 Mar 19. PMID:22334370 doi:10.1002/humu.22045
- ↑ Bartolini F, Bhamidipati A, Thomas S, Schwahn U, Lewis SA, Cowan NJ. Functional overlap between retinitis pigmentosa 2 protein and the tubulin-specific chaperone cofactor C. J Biol Chem. 2002 Apr 26;277(17):14629-34. Epub 2002 Feb 14. PMID:11847227 doi:10.1074/jbc.M200128200
- ↑ Evans RJ, Schwarz N, Nagel-Wolfrum K, Wolfrum U, Hardcastle AJ, Cheetham ME. The retinitis pigmentosa protein RP2 links pericentriolar vesicle transport between the Golgi and the primary cilium. Hum Mol Genet. 2010 Apr 1;19(7):1358-67. doi: 10.1093/hmg/ddq012. Epub 2010 Jan, 27. PMID:20106869 doi:10.1093/hmg/ddq012
- ↑ Wright KJ, Baye LM, Olivier-Mason A, Mukhopadhyay S, Sang L, Kwong M, Wang W, Pretorius PR, Sheffield VC, Sengupta P, Slusarski DC, Jackson PK. An ARL3-UNC119-RP2 GTPase cycle targets myristoylated NPHP3 to the primary cilium. Genes Dev. 2011 Nov 15;25(22):2347-60. doi: 10.1101/gad.173054.111. PMID:22085962 doi:10.1101/gad.173443.111
- ↑ Veltel S, Gasper R, Eisenacher E, Wittinghofer A. The retinitis pigmentosa 2 gene product is a GTPase-activating protein for Arf-like 3. Nat Struct Mol Biol. 2008 Apr;15(4):373-80. Epub 2008 Mar 23. PMID:18376416 doi:nsmb.1396
- ↑ Kuhnel K, Veltel S, Schlichting I, Wittinghofer A. Crystal structure of the human retinitis pigmentosa 2 protein and its interaction with Arl3. Structure. 2006 Feb;14(2):367-78. PMID:16472755 doi:10.1016/j.str.2005.11.008
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