RhoA signaling and blood pressure: The consequence of failing to “Tone it Down”

Figure 2 Multi-domain architecture of RhoGEF and RhoGAP proteins known to regulate smooth muscle cell phenotype. The catalytic domain of RhoGEFs is termed a Dbl homology (DH) domain, which serves as the major binding interface with Rho GTPases and catalyzes the dissociation of GDP from the GTPase. Pleckstrin homology (PH) domains are almost always downstream of the DH domain and these units cooperate to fully activate the GTPase. Other functional domains contained in specific RhoGEFs include the RH (Regulators of G protein Signaling Homology) domain and PDZ (Postsynaptic density 95, disk large, zona occludens-1) domain. RhoGAPs are also multi-domain containing proteins. The RhoGAP domain facilitates GTP hydrolysis and inhibits RhoA activity while other domains can regulate RhoGAP targeting and function. For example, BAR (Bin/amphiphysin/Rvs), PH, or polybasic region (PBR) domains direct lipid binding and promote membrane localization. Other domains are involved in protein-protein interactions such as GTP-binding domain (GBD), diphenylalanine motifs (FF) and the SH3 (SRC Homology 3) domains. The amino acid numbers are shown above each protein are based on the human orthologs (http://www.ncbi.nlm.nih.gov/).