STRUCTURAL MECHANISMS OF G PROTEIN ACTIVATION AND SUPPRESSION

G proteins play a central role in how cells sense and respond to their environment. Hormones, neurotransmitters, odorants, and drugs bind a large class of receptors called G protein coupled receptors (GPCRs) transverse the plasma membrane. The receptors activate intercellular G proteins, which then initiate proper cellular signaling responses. The heterotrimer consists of G subunits and an obligate dimer called G. Structural studies have revealed how G proteins interact with G proteins, receptors, RGS proteins and downstream effectors. However, the molecular events that precede heterotrimer dissociation remained poorly understood. Using cell-based assays, biochemical and structural analysis, and computational simulations, we identified a conserved triad of amino acids that governs G protein activation and subunit dissociation. Our work reveals the “G-R-E motif” exists in all known G subunits and controls the final committed step of G protein activation.Using our first endeavor as a guide, I then characterized forty G mutations that occur in a neurological condition called early infantile epileptic encephalopathy (EIEE). Go is the most abundant G protein in the brain, and defects in one of the two copies causes epileptic seizures and movement disorders. We will leverage many of the same techniques and collaborations to discern the mechanism driving the aberrant signaling. Our current project represents the most comprehensive analysis of these mutants to date, and if successful will lead to a greater understanding of how G proteins work in the brain and in human diseases.Doctor of Philosoph