Structure and Mechanism of G-proteins and cell adhesion proteins in regulation of cell growth and motility

Abstract The presented project is a comprehensive investigation encompassing two primary themes. The first theme revolves around the exploration of novel mechanisms governing the activation and signaling of guanine nucleotide-binding (G)-proteins, with a particular focus on the RAS superfamily and heterotrimeric Gα-proteins. Departing from conventional beliefs that G-protein activity is predominantly influenced by nucleotide cycling, recent findings challenge this paradigm. The project aims to delve into the regulation of inactive 'off' and active 'on' states of Gα-proteins by scrutinizing key allosteric networks within the Switch regions. Research objectives include elucidating interactions within the allosteric Switch network, investigating novel mechanisms controlling G-protein activation through pH modulation, and exploring the overlooked role of RAS-related proteins in mediating lipid kinase regulation. Employing a multidisciplinary approach that integrates computational, structural, biochemical, and cell biology methodologies, the project seeks to advance our understanding of G-protein regulation, contributing valuable insights for precision medicine strategies targeting G-protein-mediated pathologies. The second theme of the project centers on cell adhesion proteins, vinculin, and metavinculin. The investigation aims to unravel the individual and coordinated roles of these isoforms in regulating cell morphology, force transmission, and cell motility. Additionally, the project seeks to elucidate how metavinculin mutations, implicated in heart defects, disrupt adhesion site morphology and contractile force. Building on prior research into vinculin catch bonds with filamentous actin, the project expands molecular and functional studies to comprehend the collaborative roles of vinculin, metavinculin, and α-catenin in the directional and force-dependent regulation of adhesion morphology, force transmission, directed migration, and mechanosensitive diseases resulting from dysregulated mechanical cues. This dual-themed project employs a holistic and integrative approach, fostering a deeper understanding of cellular processes and providing a foundation for potential therapeutic interventions in diseases associated with G-protein and cell adhesion protein dysregulation.