RGS-CONTAINING RHOGEFS & INTERACTIONS WITH HETEROTRIMERIC & SMALL G PROTEINS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. RGS-containing RhoGEFs (RGS-RhoGEFs), including p115RhoGEF, LARG, and PDZRhoGEF, function as potential regulatory links between G protein coupled receptors that activate the G12 class of heterotrimeric G proteins and Rho-mediated pathways that lead to cytokinesis and transformation. The C-terminal halves of these RGS-RhoGEFs contain tandemly arranged Dbl homology (DH) and pleckstrin homology (PH) domains that constitute the functional unit of GEF activity in most Rho-directed GEFs. The N-terminal portions of the RGS-RhoGEFs possess RhoGEF-RGS (rgRGS) domains, some of the rgRGS domains function as GTPase activating proteins (GAPs) for Ga13. The purpose of this proposal was to determine the solution structures of the full length p115RhoGEF, its complex with activated Ga13, as well as the ternary complex of p115RhoGEF with Ga13 and RhoAas well as other family members of the RGS-RhoGEFs. We have recently purified, in large quantity, PDZRhoGEF, which does not function as a GAP for Ga13. Potentially, PDZRhoGEF could possess a different regulatory mechanism for Ga13. Hence, the solution structures of PDZRhoGEF alone, and its complex with Ga13 would be of great interest. Understanding the molecular basis by which p115RhoGEF and its homologs are regulated by G proteins should provide insight into this specific pathway for regulation as well as increase our fundamental understanding of general mechanisms of signaling by G proteins.