Crystal structure of a small G protein in complex with the GTPase-activating protein rhoGAP

Katrin Rittinger, Philip A. Walker, John F. Eccleston, Kurshid Nurmahomed, Darerca Owen, Ernest Laue, Steven J. Gamblin () and Stephen J. Smerdon
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Katrin Rittinger: National Institute for Medical Research
Philip A. Walker: National Institute for Medical Research
John F. Eccleston: National Institute for Medical Research
Kurshid Nurmahomed: National Institute for Medical Research
Darerca Owen: University of Cambridge
Ernest Laue: University of Cambridge
Steven J. Gamblin: National Institute for Medical Research
Stephen J. Smerdon: National Institute for Medical Research

Nature, 1997, vol. 388, issue 6643, 693-697

Abstract: Abstract Small G proteins transduce signals from plasma-membrane receptors to control a wide range of cellular functions1,2. These proteins are clustered into distinct families but all act as molecular switches, active in their GTP-bound form but inactive when GDP-bound. The Rho family of G proteins, which includes Cdc42Hs, activate effectors involved in the regulation of cytoskeleton formation, cell proliferation and the JNK signalling pathway3,4,5,6,7,8,9. G proteins generally have a low intrinsic GTPase hydrolytic activity but there are family-specific groups of GTPase-activating proteins (GAPs) that enhance the rate of GTP hydrolysis by up to 105times10,11. We report here the crystal structure of Cdc42Hs, with the non-hydrolysable GTP analogue GMPPNP, in complex with the GAP domain of p50rhoGAP at 2.7 å resolution. In the complex Cdc42Hs interacts, mainly through its switch I and II regions, with a shallow pocket on rhoGAP which is lined with conserved residues. Arg 85 of rhoGAP interacts with the P-loop of Cdc42Hs, but from biochemical data and by analogy with the G-protein subunit Giα1 (ref. 12), we propose that it adopts a different conformation during the catalytic cycle which enables it to stabilize the transition state of the GTP-hydrolysis reaction.

Date: 1997
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DOI: 10.1038/41805

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