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Phosphoryl transfer in Ras proteins, conclusive or elusive?
1Max-Planck-Institut für Molekulare Physiologie, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany. Alfred.Wittinghofer@mpi-dortmund.mpg.de
Trends in Biochemical Sciences
|December 17, 2005
Summary
GTP hydrolysis by Ras superfamily proteins may not share a common mechanism. A structural analysis of Rab11 suggests substrate-assisted catalysis, favoring a pentavalent phosphorane intermediate, challenging existing models of GTPase function.
Area of Science:
- Biochemistry
- Molecular Biology
- Structural Biology
Background:
- GTP hydrolysis is crucial for Ras superfamily proteins' function.
- The exact chemical mechanism and transition state of GTP hydrolysis remain debated.
- Investigating commonalities and differences in GTPase mechanisms is essential.
Purpose of the Study:
- To investigate the chemical mechanism of GTP hydrolysis in Rab11.
- To explore the nature of the transition state in GTPase reactions.
- To determine if a common GTPase mechanism exists across the Ras superfamily.
Main Methods:
- Structural analysis of Rab11.
- Analysis of GTP hydrolysis products and intermediates.
- Comparison with existing data on Ras protein reactions.
Main Results:
- An unusual configuration of the product inorganic phosphate (Pi) was observed in Rab11.
- This finding suggests substrate-assisted catalysis may facilitate nucleophilic attack.
- Evidence points towards a pentavalent phosphorane intermediate in the intrinsic GTPase reaction.
- Recent findings on GAP-mediated reactions suggest a continuum of mechanisms, not a single common one.
Conclusions:
- Substrate-assisted catalysis may be a key mechanism in intrinsic GTP hydrolysis.
- A pentavalent phosphorane intermediate is favored in the Rab11 GTPase reaction.
- A common GTPase mechanism across the Ras superfamily is unlikely, suggesting a spectrum of mechanisms.