title: Geranylgeranyl switching regulates GDI-Rab GTPase recycling.
abstract: Rab GTPases, key regulators of membrane targeting and fusion, require the covalent attachment of geranylgeranyl lipids to their C terminus for function. To elucidate the role of lipid in Rab recycling, we have determined the crystal structure of Rab guanine nucleotide dissociation inhibitor (alphaGDI) in complex with a geranylgeranyl (GG) ligand (H(2)N-Cys-(S-GG)-OMe). The lipid is bound beneath the Rab binding platform in a shallow hydrophobic groove. Mutation of the binding pocket in the brain-specific alphaGDI leads to mental retardation. Strikingly, lipid binding acts through a conserved allosteric switching mechanism to promote release of the GDI-Rab[GDP] complex from the membrane.
authors.affiliation: The Scripps Research Institute, Department of Cell Biology, 10550 North Torrey Pines Road, La Jolla, CA 92130, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: An
authors.forename: Ying
authors.initials: Y
authors.lastname: Shao
authors.forename: Christelle
authors.initials: C
authors.lastname: Alory
authors.forename: Jeanne
authors.initials: J
authors.lastname: Matteson
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Sakisaka
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.forename: Ian A
authors.initials: IA
authors.lastname: Wilson
authors.forename: William E
authors.initials: WE
authors.lastname: Balch
mesh_terms: D004224:Diterpenes / Q000378:metabolism*; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D020730:Guanine Nucleotide Dissociation Inhibitors / Q000378:metabolism*; D007930:Leucine / Q000378:metabolism; D008024:Ligands; D050356:Lipid Metabolism; D010649:Phenylalanine / Q000378:metabolism
chemical_list: D004224:Diterpenes; C086796:GDP dissociation inhibitor 1; D020730:Guanine Nucleotide Dissociation Inhibitors; D008024:Ligands; D010649:Phenylalanine; C040155:geranylgeranic acid; D020558:GTP Phosphohydrolases; D007930:Leucine