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Ras superfamily GTPase activation and inactivation occur by canonical nucleotide exchange and GTP hydrolysis mechanisms. Despite conservation of active-site residues, the Ras-related Rab GTPase activation pathway differs from Ras and between different Rabs. Analysis of DENND1-Rab35, Rabex-Rab5, TRAPP-Rab1 and DrrA-Rab1 suggests Rabs have the potential for activation by distinct GDP-release pathways. Conserved active-site residues in the Rab switch II region stabilising the nucleotide-free form differentiate these pathways. For DENND1-Rab35 and DrrA-Rab1 the Rab active-site glutamine, often mutated to create constitutively active forms, is involved in GEF mediated GDP-release. By contrast, in Rab5 the switch II aspartate is required for Rabex mediated GDP-release. Furthermore, Rab1 switch II glutamine mutants refractory to activation by DrrA can be activated by TRAPP, showing that a single Rab can be activated by more than one mechanistically distinct GDP-release pathway. These findings highlight plasticity in the activation mechanisms of closely related Rab GTPases. DOI: http://dx.doi.org/10.7554/eLife.01623.001.

Original publication

DOI

10.7554/eLife.01623

Type

Journal article

Journal

Elife

Publication Date

11/02/2014

Volume

3

Keywords

Rab GTPase, membrane traffic, nucleotide exchange factor, Adenosine Triphosphate, Aspartic Acid, Bacterial Proteins, Catalytic Domain, DNA-Binding Proteins, Death Domain Receptor Signaling Adaptor Proteins, Enzyme Activation, Glutamine, Guanine Nucleotide Exchange Factors, HeLa Cells, Humans, Hydrolysis, Listeria, Models, Molecular, Mutagenesis, Site-Directed, Mutation, Protein Conformation, Signal Transduction, Transfection, rab GTP-Binding Proteins, rab1 GTP-Binding Proteins, rab5 GTP-Binding Proteins