Structural basis for the selective activation of rho gtpases by dbl exchange factors

Jason T. Snyder, David K. Worthylakel, Kent L. Rossman, Laurie Betts, Wendy M. Pruitt, David P. Siderovski, Channing J. Der, John Sondek

Research output: Contribution to journalArticle

166 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)468-475
Number of pages8
JournalNature Structural Biology
Volume9
Issue number6
DOIs
StatePublished - 1 Jan 2002

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    Snyder, J. T., Worthylakel, D. K., Rossman, K. L., Betts, L., Pruitt, W. M., Siderovski, D. P., Der, C. J., & Sondek, J. (2002). Structural basis for the selective activation of rho gtpases by dbl exchange factors. Nature Structural Biology, 9(6), 468-475. https://doi.org/10.1038/nsb796