Geranylgeranyl switching regulates GDI-Rab GTPase recycling.
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.
An
Yu
Y
The Scripps Research Institute, Department of Cell Biology, 10550 North Torrey Pines Road, La Jolla, CA 92130, USA.
Shao
Ying
Y
Alory
Christelle
C
Matteson
Jeanne
J
Sakisaka
Toshiaki
T
Chen
Wei
W
Gibbs
Richard A
RA
Wilson
Ian A
IA
Balch
William E
WE
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
D004224:Diterpenes; C086796:GDP dissociation inhibitor 1; D020730:Guanine Nucleotide Dissociation Inhibitors; D008024:Ligands; D010649:Phenylalanine; C040155:geranylgeranic acid; D020558:GTP Phosphohydrolases; D007930:Leucine