Nature Structural Biology9, 468 - 475 (2002)
Published online: 13 May 2002; | doi:10.1038/nsb796
Structural basis for the selective activation of Rho GTPases by Dbl exchange factors
Jason T. Snyder1, 3, David K. Worthylake2, 3, Kent L. Rossman1, 3, Laurie Betts2, 3, Wendy M. Pruitt2, 3, David P. Siderovski2, 3, Channing J. Der2, 3
& John Sondek1, 2, 3
1
Department of Biochemistry and Biophysics, Program in Molecular and Cellular Biophysics, Chapel Hill, North Carolina 27599, USA.
2
Department of Pharmacology, University of North Carolina at Chapel Hill, Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina 27599, USA.
Activation of Rho-family GTPases involves the removal of bound GDP and the subsequent loading of GTP, all catalyzed by guanine nucleotide exchange factors (GEFs) of the Dbl-family. Despite high sequence conservation among Rho GTPases, Dbl proteins possess a wide spectrum of discriminatory potentials for Rho-family members. To rationalize this specificity, we have determined crystal structures of the conserved, catalytic fragments (Dbl and pleckstrin homology domains) of the exchange factors intersectin and Dbs in complex with their cognate GTPases, Cdc42 and RhoA, respectively. Structure-based mutagenesis of intersectin and Dbs reveals the key determinants responsible for promoting exchange activity in Cdc42, Rac1 and RhoA. These findings provide critical insight into the structural features necessary for the proper pairing of Dbl-exchange factors with Rho GTPases and now allow for the detailed manipulation of signaling pathways mediated by these oncoproteins in vivo.
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