Structure Elucidation of the Rho-GTPase Activating DH-Homology Domain
Annual summary rept. 1 Jun 1998-31 May 1999,
SLOAN-KETTERING INST FOR CANCER RESEARCH NEW YORK
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Guanine nucleotide exchange factors in the Dbl family activate Rho GTPases by accelerating dissociation of bound GDP, promoting acquisition of the GTP-bound state. Dbl proteins possess an approximately 200 residue catalytic Dbl-homology DH domain, that is arranged in tandem with a C-terminal pleckstrin homology PH domain in nearly all cases. Here we report the solution structure of the DH domain of human BetaPIX. The domain is composed of 11 alpha-helices that form a flattened, elongated bundle. The structure explains a large body of mutagenesis data, which, along with sequence comparisons, identify the GTPase interaction site as a surface formed by three conserved helices near the center of one face of the domain. Proximity of the site to the DH C-terminus suggests a means by which PH-ligand interactions may be coupled to DH-GTPase interactions to regulate signaling through the Dbl proteins in vivo.
- Anatomy and Physiology
- Medicine and Medical Research