Diversity and plasticity in Rab GTPase nucleotide release mechanism has consequences for Rab activation and inactivation
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Diversity and plasticity in Rab GTPase nucleotide release mechanism has consequences for Rab activation and inactivation. / Langemeyer, Lars; Nunes Bastos, Ricardo; Cai, Yiying; Itzen, Aymelt; Reinisch, Karin M; Barr, Francis A.
in: ELIFE, Jahrgang 3, 11.02.2014, S. e01623.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Diversity and plasticity in Rab GTPase nucleotide release mechanism has consequences for Rab activation and inactivation
AU - Langemeyer, Lars
AU - Nunes Bastos, Ricardo
AU - Cai, Yiying
AU - Itzen, Aymelt
AU - Reinisch, Karin M
AU - Barr, Francis A
PY - 2014/2/11
Y1 - 2014/2/11
N2 - 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.
AB - 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.
KW - Adenosine Triphosphate
KW - Aspartic Acid
KW - Bacterial Proteins
KW - Catalytic Domain
KW - DNA-Binding Proteins
KW - Death Domain Receptor Signaling Adaptor Proteins
KW - Enzyme Activation
KW - Glutamine
KW - Guanine Nucleotide Exchange Factors
KW - HeLa Cells
KW - Humans
KW - Hydrolysis
KW - Listeria
KW - Models, Molecular
KW - Mutagenesis, Site-Directed
KW - Mutation
KW - Protein Conformation
KW - Signal Transduction
KW - Transfection
KW - rab GTP-Binding Proteins
KW - rab1 GTP-Binding Proteins
KW - rab5 GTP-Binding Proteins
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.7554/eLife.01623
DO - 10.7554/eLife.01623
M3 - SCORING: Journal article
C2 - 24520163
VL - 3
SP - e01623
JO - ELIFE
JF - ELIFE
SN - 2050-084X
ER -