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 a ~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 PAK-interacting exchange protein (βPIX). The domain is composed of 11 α-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.
ASJC Scopus subject areas
- Structural Biology