Human Molecular Genetics, 2002, Vol. 11, No. 24 3065-3074
© 2002 Oxford University Press
Localization in the human retina of the X-linked retinitis pigmentosa protein RP2, its homologue cofactor C and the RP2 interacting protein Arl3
1Division of Pathology, Institute of Ophthalmology, UCL, London EC1V 9EL, UK, 2Department of Biochemistry, New York University Medical Center, New York, NY 10016, USA, 3Institute of Cancer Research, Chester Beatty Laboratories, London SW3 6JB, UK, 4Hughes Medical Institute, Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94143, USA and 5Division of Molecular Genetics, Institute of Opthalmology, UCL, London EC1V 9EL, UK
Received July 23, 2002; Accepted September 6, 2002
Mutations in the retinitis pigmentosa 2 (RP2) gene cause a severe form of X-linked retinal degeneration. RP2 is a ubiquitous 350 amino acid plasma membrane-associated protein, which shares homology with the tubulin-specific chaperone cofactor C. RP2 protein, like cofactor C, stimulates the GTPase activity of tubulin in combination with cofactor D. RP2 has also been shown to interact with ADP ribosylation factor-like 3 (Arl3) in a nucleotide and myristoylation-dependant manner. In this study we have examined the relationship between RP2, cofactor C and Arl3 in patient-derived cell lines and in the retina. Examination of lymphoblastoid cells from patients with an Arg120stop nonsense mutation in RP2 revealed that the expression levels of cofactor C and Arl3 were not affected by the absence of RP2. In human retina, RP2 was localized to the plasma membrane of cells throughout the retina. RP2 was present at the plasma membrane in both rod and cone photoreceptors, extending from the outer segment through the inner segment to the synaptic terminals. There was no enrichment of RP2 staining in any photoreceptor organelle. In contrast, cofactor C and Arl3 localized predominantly to the photoreceptor connecting cilium in rod and cone photoreceptors. Cofactor C was cytoplasmic in distribution, whereas Arl3 localized to other microtubule structures within all cells. Arl3 behaved as a microtubule-associated protein: it co-localized with microtubules in HeLa cells and this was enhanced following microtubule stabilization with taxol. Furthermore, Arl3 co-purified with microtubules from bovine brain. Following microtubule depolymerization with nocodazole, Arl3 relocalized to the nuclear membrane. These data suggest that RP2 functions in concert with Arl3 to link the cell membrane with the cytoskeleton in photoreceptors as part of the cell signaling or vesicular transport machinery.
* To whom correspondence should be addressed. Tel: +44 2076086944; Fax: +44 2076086862; Email: michael.cheetham{at}ucl.ac.uk
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