PMID- 25550383 OWN - NLM STAT- MEDLINE DCOM- 20150302 LR - 20181202 IS - 1552-5783 (Electronic) IS - 0146-0404 (Print) IS - 0146-0404 (Linking) VI - 55 IP - 12 DP - 2014 Dec 30 TI - Membrane protein transport in photoreceptors: the function of PDEdelta: the Proctor lecture. PG - 8653-66 LID - 10.1167/iovs.14-16066 [doi] AB - This lecture details the elucidation of cGMP phosphodiesterase (PDEdelta), discovered 25 years ago by Joe Beavo at the University of Washington. PDEdelta, once identified as a fourth PDE6 subunit, is now regarded as a promiscuous prenyl-binding protein and important chaperone of prenylated small G proteins of the Ras superfamily and prenylated proteins of phototransduction. Alfred Wittinghofer's group in Germany showed that PDEdelta forms an immunoglobulin-like beta-sandwich fold that is closely related in structure to other lipid-binding proteins, for example, Uncoordinated 119 (UNC119) and RhoGDI. His group cocrystallized PDEdelta with ARL (Arf-like) 2(GTP), and later with farnesylated Rheb (ras homolog expressed in brain). PDEdelta specifically accommodates farnesyl and geranylgeranyl moieties in the absence of bound protein. Germline deletion of the Pde6d gene encoding PDEdelta impeded transport of rhodopsin kinase (GRK1) and PDE6 to outer segments, causing slowly progressing, recessive retinitis pigmentosa. A rare PDE6D null allele in human patients, discovered by Tania Attie-Bitach in France, specifically impeded trafficking of farnesylated phosphatidylinositol 3,4,5-trisphosphate (PIP3) 5-phosphatase (INPP5E) to cilia, causing severe syndromic ciliopathy (Joubert syndrome). Binding of cargo to PDEdelta is controlled by Arf-like proteins, ARL2 and ARL3, charged with guanosine-5'-triphosphate (GTP). Arf-like proteins 2 and 3 are unprenylated small GTPases that serve as cargo displacement factors. The lifetime of ARL3(GTP) is controlled by its GTPase-activating protein, retinitis pigmentosa protein 2 (RP2), which accelerates GTPase activity up to 90,000-fold. RP2 null alleles in human patients are associated with severe X-linked retinitis pigmentosa (XLRP). Germline deletion of RP2 in mouse, however, causes only a mild form of XLRP. Absence of RP2 prolongs the activity of ARL3(GTP) that, in turn, impedes PDE6delta-cargo interactions and trafficking of prenylated protein to the outer segments. Hyperactive ARL3(GTP), acting as a hyperactive cargo displacement factor, is predicted to be key in the pathobiology of RP2-XLRP. CI - Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc. FAU - Baehr, Wolfgang AU - Baehr W AD - Department of Ophthalmology, John A. Moran Eye Center, University of Utah Health Science Center, University of Utah, Salt Lake City, Utah, United StatesDepartment of Neurobiology and Anatomy, University of Utah Health Science Center, University of Utah, Salt Lake City, Utah, United StatesDepartment of Biology, University of Utah, Salt Lake City, Utah, United States. LA - eng GR - R01 EY008123/EY/NEI NIH HHS/United States GR - R01 EY019298/EY/NEI NIH HHS/United States GR - EY019298/EY/NEI NIH HHS/United States GR - EY08123/EY/NEI NIH HHS/United States PT - Lecture PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20141230 PL - United States TA - Invest Ophthalmol Vis Sci JT - Investigative ophthalmology & visual science JID - 7703701 RN - 0 (Membrane Transport Proteins) RN - EC 3.1.4.35 (3',5'-Cyclic-GMP Phosphodiesterases) RN - EC 3.1.4.35 (Cyclic Nucleotide Phosphodiesterases, Type 6) RN - EC 3.6.5.1 (Transducin) RN - EC 3.6.5.2 (ADP-Ribosylation Factors) SB - IM MH - 3',5'-Cyclic-GMP Phosphodiesterases/*physiology MH - ADP-Ribosylation Factors/physiology MH - Animals MH - Biological Transport/*physiology MH - Cyclic Nucleotide Phosphodiesterases, Type 6/physiology MH - Disease Models, Animal MH - Humans MH - Membrane Transport Proteins/physiology MH - Mice MH - Photoreceptor Cells, Vertebrate/*physiology MH - Protein Prenylation/physiology MH - Transducin/metabolism MH - Vision, Ocular/*physiology PMC - PMC4541489 OTO - NOTNLM OT - phototransduction OT - protein trafficking OT - proteinprenylation EDAT- 2015/01/01 06:00 MHDA- 2015/03/03 06:00 PMCR- 2015/06/01 CRDT- 2015/01/01 06:00 PHST- 2015/01/01 06:00 [entrez] PHST- 2015/01/01 06:00 [pubmed] PHST- 2015/03/03 06:00 [medline] PHST- 2015/06/01 00:00 [pmc-release] AID - 55/12/8653 [pii] AID - 10.1167/iovs.14-16066 [doi] PST - epublish SO - Invest Ophthalmol Vis Sci. 2014 Dec 30;55(12):8653-66. doi: 10.1167/iovs.14-16066.