STRUCTURAL STUDIES OF RHO-FAMILY SMALL G-PROTEIN ACTIVATION

Katrin Rittinger, Philip A. Walker, John F. Eccleston, Aldo Tarricone, Steven J. Gamblin and Stephen J. Smerdon.

National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK

Small G-proteins of the rho family, which includes rho, rac and cdc42, regulate phosphorylation pathways that control a plethora of biological functions including cytoskeleton formation and cell proliferation. They operate as molecular switches, cycling between the biologically active GTP-bound form and the inactive GDP-bound state. Their intrinsic GTPase rate is slow but can be accelerated by up to 10⁵ fold by interaction with rhoGAP. As such, rhoGAP plays a crucial role in regulating rho-mediated signalling pathways. We have determined crystal structures of rhoGAP and its complexes with cdc42.GMPPNP and rhoA.GDP.AlF₄^-, a transition state analogue of the GTP hydrolysis reaction^1-3. These studies, in combination with those of ras activation by rasGAP^4,5 have provided invaluable insights into the molecular basis of regulation of small G-proteins.

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