Biology:Retinitis pigmentosa GTPase regulator

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
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

  1. ↑ "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. 
  2. ↑ "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. 
  3. ↑ "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. ↑ 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. ↑ 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. ↑ 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. 
  7. ↑ "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. ↑ 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
  9. ↑ "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. 
  10. ↑ "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. 
  11. ↑ "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. 
  12. ↑ "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. 
  13. ↑ "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. 
  14. ↑ "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. 
  15. ↑ "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. 
  16. ↑ 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




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