Biology:Retinitis pigmentosa GTPase regulator
 Generic protein structure example |
X-linked retinitis pigmentosa GTPase regulator is a GTPase-binding protein that in humans is encoded by the RPGR gene.[1][2][3][4] The gene is located on the X-chromosome and is commonly associated with X-linked retinitis pigmentosa (XLRP). In photoreceptor cells, RPGR is localized in the connecting cilium which connects the protein-synthesizing inner segment to the photosensitive outer segment and is involved in the modulation of cargo trafficked between the two segments.[5]
Function
This gene encodes a protein with a series of six RCC1-like domains (RLDs), characteristic of the highly conserved guanine nucleotide exchange factors. Mutations in this gene have been associated with X-linked retinitis pigmentosa (XLRP). Multiple alternatively spliced transcript variants that encode different isoforms of this gene have been reported, but the full-length natures of only some have been determined.[4]
The two major isoforms are RPGRconst, the default isoform, composed of exons 1-19, and RPGRORF15 which retains part of intron 15 as the terminal exon. ORF15 is the terminal exon of RPGRORF15 and is a mutational hotspot accounting for ~60% of RPGR patients with heterogeneous diseases ranging from XLRP to cone-rod degeneration and macular degeneration.[6] Alternatively, the RPGRconst isoform contains a putative prenylation domain on its C-terminal end[6] which is involved in posttranslational modification and allows membrane-association and protein trafficking.[7] The C-terminal domain of the RPGRconst isoform contains a CTIL motif (812CTIL815) which recruits prenyl-binding protein PDE6D which then shuttles the protein to the connecting cilium.[8]
Photoreceptor cells contain an inner segment and an outer segment which are joined by a connecting cilium. Protein synthesis occurs exclusively in the inner segment and all proteins must be trafficked across the connecting cilium to the outer segment where the phototransduction cascade takes place. RPGR is primarily located in a protein complex in the connecting cilium and is involved in regulating the cargo that is trafficked from the inner segment to the outer segment.[5]
Interactions
Retinitis pigmentosa GTPase regulator has been shown to interact with PDE6D[9] nephronophthisis (NPHP) proteins[10] and RPGRIP1.[11] Binding to PDE6D has been shown to ensure ciliary localization of the RPGRconst isoform.[12] Additionally, the N-terminal of interacts with a PDE6D interacting proetin, INPP5E (inositol polyphosphatase 5E).[8] INPP5E has been shown to regulates phosphoinositide metabolism and may modulate the phosphoinositide content of photoreceptors.[5]
RPGR has also been shown to preferentially interact with the GDP-bound form of the small GTPase RAB8A.[13] RAB8A is involved in rhodopsin trafficking in primary cilia.[14] The C-terminal domain of RPGRORF15 has been shown to interact with whirlin, a ciliary protein that is mutated in Usher Syndrome.[15] The RPGRORF15 isoform has been shown to be glutamylated on its N-terminus by tubulin-tyrosine ligase-like 5 (TTLL5).[16] It has also been shown that loss of TTLL5 mimics loss of RPGR in the mouse retina.
See also
References
- ↑ "A gene (RPGR) with homology to the RCC1 guanine nucleotide exchange factor is mutated in X-linked retinitis pigmentosa (RP3)". Nature Genetics 13 (1): 35–42. May 1996. doi:10.1038/ng0596-35. PMID 8673101.
- ↑ "Positional cloning of the gene for X-linked retinitis pigmentosa 3: homology with the guanine-nucleotide-exchange factor RCC1". Human Molecular Genetics 5 (7): 1035–41. Jul 1996. doi:10.1093/hmg/5.7.1035. PMID 8817343.
- ↑ "Interaction of retinitis pigmentosa GTPase regulator (RPGR) with RAB8A GTPase: implications for cilia dysfunction and photoreceptor degeneration". Human Molecular Genetics 19 (18): 3591–8. Sep 2010. doi:10.1093/hmg/ddq275. PMID 20631154.
- ↑ 4.0 4.1 "Entrez Gene: RPGR retinitis pigmentosa GTPase regulator". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6103.
- ↑ 5.0 5.1 5.2 "Photoreceptor Sensory Cilium: Traversing the Ciliary Gate". Cells 4 (4): 674–86. October 2015. doi:10.3390/cells4040674. PMID 26501325.
- ↑ 6.0 6.1 "Mutations in the X-linked retinitis pigmentosa genes RPGR and RP2 found in 8.5% of families with a provisional diagnosis of autosomal dominant retinitis pigmentosa". Investigative Ophthalmology & Visual Science 54 (2): 1411–6. February 2013. doi:10.1167/iovs.12-11541. PMID 23372056.
- ↑ "Role of protein modification reactions in programming interactions between ras-related GTPases and cell membranes". Annual Review of Cell Biology 10: 181–205. 1994. doi:10.1146/annurev.cb.10.110194.001145. PMID 7888176.
- ↑ 8.0 8.1 Rao KN, Zhang W, Li L, Anand M, Khanna H (2016b) Prenylated retinal ciliopathy protein RPGR interacts with PDE6delta and regulates ciliary localization of Joubert syndrome-associated protein INPP5E. Hum Mol Genet 25(20):4533–4545
- ↑ "The retinitis pigmentosa GTPase regulator, RPGR, interacts with the delta subunit of rod cyclic GMP phosphodiesterase". Proceedings of the National Academy of Sciences of the United States of America 96 (4): 1315–20. Feb 1999. doi:10.1073/pnas.96.4.1315. PMID 9990021. Bibcode: 1999PNAS...96.1315L.
- ↑ "Interaction of ciliary disease protein retinitis pigmentosa GTPase regulator with nephronophthisis-associated proteins in mammalian retinas". Molecular Vision 16: 1373–81. July 2010. PMID 20664800.
- ↑ "The retinitis pigmentosa GTPase regulator (RPGR) interacts with novel transport-like proteins in the outer segments of rod photoreceptors". Human Molecular Genetics 9 (14): 2095–105. Sep 2000. doi:10.1093/hmg/9.14.2095. PMID 10958648.
- ↑ "Ciliopathy-associated protein CEP290 modifies the severity of retinal degeneration due to loss of RPGR". Human Molecular Genetics 25 (10): 2005–2012. May 2016. doi:10.1093/hmg/ddw075. PMID 26936822.
- ↑ "Molecular complexes that direct rhodopsin transport to primary cilia". Progress in Retinal and Eye Research 38: 1–19. January 2014. doi:10.1016/j.preteyeres.2013.08.004. PMID 24135424.
- ↑ "Mutant rab8 Impairs docking and fusion of rhodopsin-bearing post-Golgi membranes and causes cell death of transgenic Xenopus rods". Molecular Biology of the Cell 12 (8): 2341–51. August 2001. doi:10.1091/mbc.12.8.2341. PMID 11514620.
- ↑ "A novel gene for Usher syndrome type 2: mutations in the long isoform of whirlin are associated with retinitis pigmentosa and sensorineural hearing loss". Human Genetics 121 (2): 203–11. April 2007. doi:10.1007/s00439-006-0304-0. PMID 17171570.
- ↑ Sun X, Park JH, Gumerson J, Wu Z, Swaroop A, Qian H, Roll-Mecak A, Li T (2016) Loss of RPGR glutamylation underlies the pathogenic mechanism of retinal dystrophy caused by TTLL5 mutations. Proc Natl Acad Sci U S A 113:E2925–E2934
Further reading
- "RCC1-like domain and ORF15: essentials in RPGR gene". Retinal Degenerative Diseases. Advances in Experimental Medicine and Biology. 572. 2007. pp. 29–33. doi:10.1007/0-387-32442-9_5. ISBN 978-0-387-28464-4. https://archive.org/details/isbn_9780387284644/page/29.
- "Localizing multiple X chromosome-linked retinitis pigmentosa loci using multilocus homogeneity tests". Proceedings of the National Academy of Sciences of the United States of America 87 (2): 701–4. Jan 1990. doi:10.1073/pnas.87.2.701. PMID 2300556. Bibcode: 1990PNAS...87..701O.
- "X-linked dominant cone-rod degeneration: linkage mapping of a new locus for retinitis pigmentosa (RP 15) to Xp22.13-p22.11". American Journal of Human Genetics 57 (1): 87–94. Jul 1995. PMID 7611300.
- "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene 138 (1–2): 171–4. Jan 1994. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
- "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Research 6 (9): 791–806. Sep 1996. doi:10.1101/gr.6.9.791. PMID 8889548.
- "Analysis of the RPGR gene in 11 pedigrees with the retinitis pigmentosa type 3 genotype: paucity of mutations in the coding region but splice defects in two families". American Journal of Human Genetics 61 (3): 571–80. Sep 1997. doi:10.1086/515523. PMID 9326322.
- "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene 200 (1–2): 149–56. Oct 1997. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
- "Spectrum of mutations in the RPGR gene that are identified in 20% of families with X-linked retinitis pigmentosa". American Journal of Human Genetics 61 (6): 1287–92. Dec 1997. doi:10.1086/301646. PMID 9399904.
- "Localization of CSNBX (CSNB4) between the retinitis pigmentosa loci RP2 and RP3 on proximal Xp". Investigative Ophthalmology & Visual Science 38 (13): 2750–5. Dec 1997. PMID 9418727.
- "Biochemical characterization and subcellular localization of the mouse retinitis pigmentosa GTPase regulator (mRpgr)". The Journal of Biological Chemistry 273 (31): 19656–63. Jul 1998. doi:10.1074/jbc.273.31.19656. PMID 9677393.
- "X-linked retinitis pigmentosa in two families with a missense mutation in the RPGR gene and putative change of glycine to valine at codon 60". Ophthalmology 105 (12): 2286–96. Dec 1998. doi:10.1016/S0161-6420(98)91231-3. PMID 9855162.
- "The retinitis pigmentosa GTPase regulator, RPGR, interacts with the delta subunit of rod cyclic GMP phosphodiesterase". Proceedings of the National Academy of Sciences of the United States of America 96 (4): 1315–20. Feb 1999. doi:10.1073/pnas.96.4.1315. PMID 9990021. Bibcode: 1999PNAS...96.1315L.
- "Identification of a 5' splice site mutation in the RPGR gene in a family with X-linked retinitis pigmentosa (RP3)". Human Mutation 13 (2): 141–5. 1999. doi:10.1002/(SICI)1098-1004(1999)13:2<141::AID-HUMU6>3.0.CO;2-Q. PMID 10094550.
- "RPGR transcription studies in mouse and human tissues reveal a retina-specific isoform that is disrupted in a patient with X-linked retinitis pigmentosa". Human Molecular Genetics 8 (8): 1571–8. Aug 1999. doi:10.1093/hmg/8.8.1571. PMID 10401007.
- "Identification of novel RPGR (retinitis pigmentosa GTPase regulator) mutations in a subset of X-linked retinitis pigmentosa families segregating with the RP3 locus". Human Genetics 105 (1–2): 57–62. 1999. doi:10.1007/s004390051064. PMID 10480356.
- "Mutation analysis of the RPGR gene reveals novel mutations in south European patients with X-linked retinitis pigmentosa". European Journal of Human Genetics 7 (6): 687–94. Sep 1999. doi:10.1038/sj.ejhg.5200352. PMID 10482958.
- "A retinitis pigmentosa GTPase regulator (RPGR)-deficient mouse model for X-linked retinitis pigmentosa (RP3)". Proceedings of the National Academy of Sciences of the United States of America 97 (7): 3649–54. Mar 2000. doi:10.1073/pnas.060037497. PMID 10725384.
- "Novel mutations of the RPGR gene in RP3 families". Human Mutation 15 (4): 386. Apr 2000. doi:10.1002/(SICI)1098-1004(200004)15:4<386::AID-HUMU23>3.0.CO;2-4. PMID 10737996.
- "Ablation of retinal ciliopathy protein RPGR results in altered photoreceptor ciliary composition". Scientific Reports 5: 11137. 2015. doi:10.1038/srep11137. PMID 26068394. Bibcode: 2015NatSR...511137R.
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