- The retinitis pigmentosa 2 polypeptide (RP2) functions as a GTPase-activating protein (GAP) for ARL3 (Arf-like protein 3), a small GTPase. ARL3 is an effector of phosphodiesterase 6 Delta (PDE6D), a prenyl-binding protein and chaperone of prenylated protein in photoreceptors. Mutations in the human RP2 gene cause X-linked retinitis pigmentosa (XLRP) and cone-rod dystrophy (XL-CORD). To study mechanisms causing XLRP, we generated an RP2 knockout mouse. The RP2h(-/-) mice exhibited a slowly progressing rod-cone dystrophy simulating the human disease. RP2h(-/-) scotopic a-wave and photopic b-wave amplitudes declined at 1 mo of age and continued to decline over the next 6 mo. Prenylated PDE6 subunits and G-protein coupled receptor kinase 1 (GRK1) were unable to traffic effectively to the RP2h(-/-) outer segments. Mechanistically, absence of RP2 GAP activity increases ARL3-GTP levels, forcing PDE6D to assume a predominantly "closed" conformation that impedes binding of lipids. Lack of interaction disrupts trafficking of PDE6 and GRK1 toThe retinitis pigmentosa 2 polypeptide (RP2) functions as a GTPase-activating protein (GAP) for ARL3 (Arf-like protein 3), a small GTPase. ARL3 is an effector of phosphodiesterase 6 Delta (PDE6D), a prenyl-binding protein and chaperone of prenylated protein in photoreceptors. Mutations in the human RP2 gene cause X-linked retinitis pigmentosa (XLRP) and cone-rod dystrophy (XL-CORD). To study mechanisms causing XLRP, we generated an RP2 knockout mouse. The RP2h(-/-) mice exhibited a slowly progressing rod-cone dystrophy simulating the human disease. RP2h(-/-) scotopic a-wave and photopic b-wave amplitudes declined at 1 mo of age and continued to decline over the next 6 mo. Prenylated PDE6 subunits and G-protein coupled receptor kinase 1 (GRK1) were unable to traffic effectively to the RP2h(-/-) outer segments. Mechanistically, absence of RP2 GAP activity increases ARL3-GTP levels, forcing PDE6D to assume a predominantly "closed" conformation that impedes binding of lipids. Lack of interaction disrupts trafficking of PDE6 and GRK1 to their destination, the photoreceptor outer segments. We propose that hyperactivity of ARL3-GTP in RP2 knockout mice and human patients with RP2 null alleles leads to XLRP resembling recessive rod-cone dystrophy.…
MetadatenAuthor details: | Houbin ZhangORCiD, Christin Hanke-Gogokhia, Li JiangORCiD, Xiaobo Li, Pu Wang, Cecilia D. Gerstner, Jeanne M. Frederick, Zhenglin Yang, Wolfgang BaehrORCiD |
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DOI: | https://doi.org/10.1096/fj.14-257915 |
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ISSN: | 0892-6638 |
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ISSN: | 1530-6860 |
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Pubmed ID: | https://pubmed.ncbi.nlm.nih.gov/25422369 |
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Title of parent work (English): | The FASEB journal : the official journal of the Federation of American Societies for Experimental Biology |
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Publisher: | Federation of American Societies for Experimental Biology |
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Place of publishing: | Bethesda |
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Publication type: | Article |
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Language: | English |
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Year of first publication: | 2015 |
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Publication year: | 2015 |
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Release date: | 2017/03/27 |
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Tag: | ARL3; PDE6D; RP2; XLRP; rod-cone dystrophy |
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Volume: | 29 |
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Issue: | 3 |
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Number of pages: | 11 |
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First page: | 932 |
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Last Page: | 942 |
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Funding institution: | U.S. National Institutes of Health [EY020969, EY08123, EY019298,
EY014800-039003]; National Science Foundation [NSFC81371030]; Research
to Prevent Blindness; RPB Nelson Trust Award |
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Organizational units: | Mathematisch-Naturwissenschaftliche Fakultät / Institut für Biochemie und Biologie |
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Peer review: | Referiert |
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