Structural Features of RhoGEFs

This chapter surveys the structural features of RhoGEFs and highlights the key determinants responsible for dictating the activation of Rho GTPases. Dbl family proteins are the major recognized class of GEFs for the Rho family of small GTPases. Rho GTPases have risen to prominence since a large body of work over the last ten years has implicated these ∼25-kDa members of the Ras superfamily in controlling vital cellular functions, including organization of the actin cytoskeleton, progression through the cell cycle, and regulation of transcriptional activities. Given that Rho GTPases manage various critical cellular processes, it is not surprising that these small GTPases, as well as their activators (RhoGEFs), promote oncogenesis when constitutively activated. Membership within the Dbl family of RhoGEFs is solely dependent upon the possession of an -300 amino acid segment containing a Dbl homology (DH) domain directly adjacent to a pleckstrin homology (PH) domain. While PH domains exist in a multitude of signaling proteins, the DH domain is unique to these RhoGEFs, and accordingly constitutes the primary catalytic portion of a Dbl protein by supporting nucleotide exchange activity within a substrate Rho GTPase in vitro and in vivo . Recent biophysical investigations into the function of Dbl-family proteins have revealed substantial insight into the means by which these RhoGEFs catalyze the removal of bound nucleotide from Rho proteins. Specifically, an understanding at atomic resolution of the roles of the conserved DH and PH domains found within all Dbl-related proteins is now available.