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Prepublished online as a Blood First Edition Paper on November 21, 2002; DOI 10.1182/blood-2002-09-2789. This Article Full Text Full Text (PDF) All Versions of this Article: 2002-09-2789v1 101/7/2736    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Ménasché, G. Articles by Basile, G. d. S. Search for Related Content PubMed PubMed Citation Articles by Ménasché, G. Articles by Basile, G. d. S. Related Collections Clinical Trials and Observations Immunobiology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 April 2003, Vol. 101, No. 7, pp. 2736-2742 IMMUNOBIOLOGY Biochemical and functional characterization of Rab27a mutations occurring in Griscelli syndrome patients Gaël Ménasché, Jérôme Feldmann, Anne Houdusse, Catherine Desaymard, Alain Fischer, Bruno Goud, and Geneviève de Saint Basile From the Unité de Recherche sur le Développement Normal et Pathologique du Système Immunitaire Institut National de la Santé et de la Recherche Médicale (INSERM) U429, Hôpital Necker-Enfants Malades, Paris, France; and équipe Motilité structurale and équipe Mécanismes moléculaires du transport intracellulaire, Unité Mixte de Recherche, Institut Curie/Centre National de la Recherche Scientifique 144, Institut Curie, Paris, France. Rab27a is a member of the Rab family of small GTPase proteins, and thus far is the first member to be associated with a human disease (ie, the Griscelli syndrome type 2). Mutations in the Rab27a gene cause pigment as well as cytotoxic granule transport defects, accounting for the partial albinism and severe immune disorder characteristics of this syndrome. So far, 3 Rab27a missense mutations have been identified. They open a unique opportunity to designate critical structural and functional residues of Rab proteins. We show here that the introduction of a proline residue in the 4 (Ala152Pro) or 5 (Leu130Pro) loop, observed in 2 of these spontaneous mutants, dramatically affects both guanosine triphosphate (GTP) and guanosine diphosphate (GDP) nucleotide-binding activity of Rab27a, probably by disrupting protein folding. The third mutant, Trp73Gly, is located within an invariant hydrophobic triad at the switch interface, and was previously shown in active Rab3A to mediate rabphilin3A effector interaction. Trp73Gly is shown to display the same nucleotide-binding and GTPase characteristics as the constitutively active mutant Gln78Leu. However, in contrast to Gln78Leu, Trp73Gly mutant construct neither interacts with the Rab27a effector melanophilin nor modifies melanosome distribution and cytotoxic granule exocytosis. Substitutions introduced at the 73 position, including the leucine residue present in Ras, did not restore Rab27a protein functions. Taken together, our results characterize new critical residues of Rab proteins, and identify the Trp73 residue of Rab27a as a key position for interaction with the specific effectors of Rab27a, both in melanocytes and cytotoxic cells. © 2003 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: H. Higashio, N. Nishimura, H. Ishizaki, J. Miyoshi, S. Orita, A. Sakane, and T. Sasaki Doc2{alpha} and Munc13-4 Regulate Ca2+-Dependent Secretory Lysosome Exocytosis in Mast Cells J. Immunol., April 1, 2008; 180(7): 4774 - 4784. [Abstract] [Full Text] [PDF] P. D. Fairbank, C. Lee, A. Ellis, J. D. Hildebrand, J. M. Gross, and J. B. Wallingford Shroom2 (APXL) regulates melanosome biogenesis and localization in the retinal pigment epithelium Development, October 15, 2006; 133(20): 4109 - 4118. [Abstract] [Full Text] [PDF] M. L. Chabrillat, C. Wilhelm, C. Wasmeier, E. V. Sviderskaya, D. Louvard, and E. Coudrier Rab8 Regulates the Actin-based Movement of Melanosomes Mol. Biol. Cell, April 1, 2005; 16(4): 1640 - 1650. [Abstract] [Full Text] [PDF] F. L. Meyskens Jr., P. J. Farmer, and H. Anton-Culver Etiologic Pathogenesis of Melanoma: A Unifying Hypothesis for the Missing Attributable Risk Clin. Cancer Res., April 15, 2004; 10(8): 2581 - 2583. [Full Text] [PDF] M. Fukuda and T. S. Kuroda Missense mutations in the globular tail of myosin-Va in dilute mice partially impair binding of Slac2-a/melanophilin J. Cell Sci., February 15, 2004; 117(4): 583 - 591. [Abstract] [Full Text] [PDF] C. Desnos, J.-S. Schonn, S. Huet, V. S. Tran, A. El-Amraoui, G. Raposo, I. Fanget, C. Chapuis, G. Menasche, G. de Saint Basile, et al. Rab27A and its effector MyRIP link secretory granules to F-actin and control their motion towards release sites J. Cell Biol., November 10, 2003; 163(3): 559 - 570. [Abstract] [Full Text] [PDF] T. S. Kuroda, H. Ariga, and M. Fukuda The Actin-Binding Domain of Slac2-a/Melanophilin Is Required for Melanosome Distribution in Melanocytes Mol. Cell. Biol., August 1, 2003; 23(15): 5245 - 5255. [Abstract] [Full Text] [PDF]

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