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♦ See referenced article, J. Biol. Chem. 2010, 285, 21070–21081
Guanine nucleotide exchange factors (GEFs) catalyze the GDP/GTP exchange of GTPase enzymes by stabilizing the nucleotide-free state of GTPases through their Dbl homology (DH) and pleckstrin homology (PH) domains. PDZ-RhoGEF (PRG) is a member of the RGS-RhoGEF family and functions in the regulation of cell motility. PRG contains an additional regulator of G protein signaling (RGS) domain. Thus it can bind to both nucleotide-free and GTP-activated RhoA. In this Paper of the Week, Zhe Chen and colleagues, in an effort to characterize this unconventional interaction, have solved the structure of the PRG-DH·PH domains in complex with activated RhoA. They found that the PRG-DH·PH-RhoA·GTPγS interface was strikingly similar to that of a GTPase-effector complex, involving the switch regions in RhoA and a conserved hydrophobic patch in the PH domain. This region did not overlap with the DH·PH surface that binds nucleotide-free RhoA, thus enabling PRG-DH·PH to bind to both forms of RhoA at the same time. The novel interaction revealed in this study supports the idea that the spatial and temporal regulation of G protein signaling may involve a more complex mechanism than currently believed.