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Ocular albinism: evidence for a defect in an intracellular signal transduction system

Nature Genetics volume 23, pages 108–112 (1999)Cite this article

Abstract

G protein-coupled receptors (GPCRs) participate in the most common signal transduction system at the plasma membrane1. The wide distribution of heterotrimeric G proteins in the internal membranes suggests that a similar signalling mechanism might also be used at intracellular locations2. We provide here structural evidence that the protein product of the ocular albinism type 1 gene (OA1), a pigment cell-specific integral membrane glycoprotein3, represents a novel member of the GPCR superfamily and demonstrate that it binds heterotrimeric G proteins. Moreover, we show that OA1 is not found at the plasma membrane, being instead targeted to specialized intracellular organelles, the melanosomes. Our data suggest that OA1 represents the first example of an exclusively intracellular GPCR and support the hypothesis that GPCR-mediated signal transduction systems also operate at the internal membranes in mammalian cells.

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Figure 1: Primary sequence similarities between OA1 and related GPCRs.
Figure 2: Heterotrimeric G protein co-immunoprecipitation with OA1 in normal human melanocytes (a) and transfected COS-7 cells (b).
Figure 3: Heterotrimeric G protein in vitro binding to OA1 in normal human melanocyte extracts.
Figure 4: Melanosomal localization of OA1 and heterotrimeric Gi proteins.
Figure 5: Cell surface biotinylation of normal human melanocytes.
Figure 6: Lysosomal localization of OA1 in transiently transfected COS-7 cells.

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Acknowledgements

We thank M. Fabbri and R. Halaban for anti-β1 integrin subunit and anti-tyrosinase antibodies, respectively; P. De Camilli, S. Colamarino, I. De Curtis, V. Marigo, R. Pardi, E. Rugarli, S. Schiaffino, R. Sitia and L. Vallar for helpful suggestions; T.E. Kreis for the use of epifluorescence microscopy and camera equipment; and A.A. Mironov for the immunoperoxidase staining method. The support of the Vision of Children (San Diego) and the Italian Telethon Foundation (grants E.583, A.41 and A.106) is gratefully acknowledged. This work was also supported by Ministero della Ricerca Scientifica (MURST) and by Consiglio Nazionale delle Ricerche (CNR finalizzato "Biotecnologie"), Italy, and by EEC Biomed 2 grant no. BMHG4-97-2062.

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Authors and Affiliations

  1. Telethon Institute of Genetics and Medicine, Milan, 20132

    M. Vittoria Schiaffino, Marilena d'Addio, Anna Alloni, Cinzia Baschirotto, M. Teresa Bassi, Cristina Colla & Andrea Ballabio

  2. Department of Experimental Medicine, Anatomy Section, University of Genoa, Genoa, 16132

    Caterina Valetti, Katia Cortese, Claudia Puri & Carlo Tacchetti

  3. IDI-IRCCS, Istituto Dermopatico dell'Immacolata, Rome, 00167

    Michele De Luca

  4. Universita' Vita-Salute San Raffaele, Milan, 20132, Italy

    Andrea Ballabio

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  1. M. Vittoria Schiaffino
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Correspondence to M. Vittoria Schiaffino.

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Schiaffino, M., d'Addio, M., Alloni, A. et al. Ocular albinism: evidence for a defect in an intracellular signal transduction system. Nat Genet 23, 108–112 (1999). https://doi.org/10.1038/12715

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