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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 (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 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 Menasche, G. Articles by de Saint Basile, G. Search for Related Content PubMed PubMed Citation Articles by Menasche, G. Articles by de Saint Basile, G. Social Bookmarking                   What's this? Submitted September 13, 2002 Accepted November 12, 2002 Biochemical and functional charaterization of Rab27a mutations occurring in Griscelli syndrome patients Gael Menasche, Jerome Feldmann, Anne Houdusse, Catherine Desaymard, Alain Fischer, Bruno Goud, and Genevieve de Saint Basile* Unite 429, INSERM, Paris, France Equipe Motilite Structurale, I.Curie/CNRS 144, Paris, France Equipe Mecanisme Moleculaire du Transport Intracellulaire, I.Curie/CNRS 144, Paris, France * Corresponding author; email: sbasile{at}necker.fr. Rab27a is a member of the Rab family of small GTPase protein, the first member of this protein family so far associated with a human disease, i.e. the Griscelli syndrome type 2. Mutations in Rab27a gene cause pigment as well as cytotoxic granule transport defects accounting for the partial albinism and severe immune disorder characteristic of this disorder. So far, three 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 a4 (A152P) or 5 (L130P) loop observed in two of these spontaneous mutants, dramatically affects both GTP and GDP nucleotide binding activity of Rab27a, probably by disrupting protein folding. The third mutant, W73G, is located within an invariant hydrophobic triad at the switch interface, previously shown in active Rab3A to mediate Rabphilin3A effector interaction. W73G is shown to display the same nucleotide binding and GTPase characteristics as the constitutively active mutant Q78L. However, in contrast to Q78L, W73G 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 L residue present in Ras, did not restore Rab27a protein functions. Taken together, our results characterize new critical residues of Rab proteins, and identify the W73 residue of Rab27a as a key position for interaction with the specific effectors of Rab27a, both in melanocytes and cytotoxic cells. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: G. Menasche, M. M. Menager, J. M. Lefebvre, E. Deutsch, R. Athman, N. Lambert, N. Mahlaoui, M. Court, J. Garin, A. Fischer, et al. A newly identified isoform of Slp2a associates with Rab27a in cytotoxic T cells and participates to cytotoxic granule secretion Blood, December 15, 2008; 112(13): 5052 - 5062. [Abstract] [Full Text] [PDF] 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. 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