Abstract 2033 How G proteins work and what happens when they don't

Most hormones, neurotransmitters, and environmental signals, as well as a large proportion of all pharmaceuticals, exert their effects through G protein-coupled receptors. These receptors promote GTP binding to the G protein and dissociation of the constituent subunits. Receptor action is opposed by regulators of G protein signaling, which accelerate GTP hydrolysis. This cycle of G protein activation and inactivation has been extensively characterized using biochemical, cellular, and structural approaches. Complementing these efforts, much has been learned through molecular analysis of G protein mutants responsible for cancer as well as movement, endocrine and developmental disorders. Most prominently, these are uveal melanoma (affecting Gq) and developmental epileptic encephalopathy (affecting Gq). Whereas some disease mutations lock the G protein in either the apo, GTP- or GDP-bound states, others block association with GTPase-activating proteins or prevent dissociation of the G protein subunits. Mechanistic evaluation of these mutants has yielded a powerful and well-validated molecular toolkit for investigating – structurally and functionally - individual steps of the G protein activation cycle, and are likely to accelerate drug screening efforts in the years ahead. NIH R35GM118105.