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| Subject Categories: Structural Biology | Signal Transduction |
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| The EMBO Journal
(2002) 21, 1315–1326, doi: 10.1093/emboj/21.6.1315 |
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| A crystallographic view of interactions between Dbs and Cdc42: PH domain-assisted guanine nucleotide exchange |
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| Kent L. Rossman1, David K. Worthylake2, Jason T. Snyder1, David P. Siderovski2, 3, Sharon L. Campbell1, 3 and John Sondek1, 2, 3 |
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1 Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA 2 Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, USA 3 Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA To whom correspondence should be addressed John Sondek, sondek@med.unc.edu Received 17 February 2001; Revised 21 January 2002; Accepted 21 January 2002. |
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| Abstract |
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Dbl-related oncoproteins are guanine nucleotide exchange factors (GEFs) specific for Rho guanosine triphosphatases (GTPases) and invariably possess tandem Dbl (DH) and pleckstrin homology (PH) domains. While it is known that the DH domain is the principal catalytic subunit, recent biochemical data indicate that for some Dbl-family proteins, such as Dbs and Trio, PH domains may cooperate with their associated DH domains in promoting guanine nucleotide exchange of Rho GTPases. In order to gain an understanding of the involvement of these PH domains in guanine nucleotide exchange, we have determined the crystal structure of a DH/PH fragment from Dbs in complex with Cdc42. The complex features the PH domain in a unique conformation distinct from the PH domains in the related structures of Sos1 and Tiam1 Rac1. Consequently, the Dbs PH domain participates with the DH domain in binding Cdc42, primarily through a set of interactions involving switch 2 of the GTPase. Comparative sequence analysis suggests that a subset of Dbl-family proteins will utilize their PH domains similarly to Dbs. |
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| Keywords: Dbs, DH domain, PH domain, Rho GEF, Rho GTPase |
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