Allosteric activation of heterotrimeric G-proteins by GPCRs is crucial for transmitting extracellular stimuli into intracellular signaling cascades important for diverse biological processes including vision, neurotransmission, olfaction and cell division. In human, 16 different isoforms of G-proteins that belong to 4 distinct subfamilies are allosterically activated by more than 800 GPCRs in response to external stimuli. Dysfunctional GPCR-signaling as well as constitutively active mutants of G-proteins are responsible for various disease conditions. Understanding allosteric dynamics of G-protein activation and its features conserved across subfamilies can reveal a common mechanism for targeting G-protein signaling pathways. In this work, we investigate the dynamics of allosteric activation in 6 distinct G-protein isoforms spanning all 4 subfamilies using over 210 microseconds of molecular dynamics simulations. By comparing the dynamics of these isoforms, we identify conserved features of the allosteric communication network in G-proteins. We experimentally test the importance of residues forming the conserved allosteric network and propose dominant allosteric pathways in G-protein activation. The conserved allosteric network identified in this work also includes known disease mutations, which could provide a foundation for deactivating disease mutations.

Activation of distinct G protein isoforms employs a conserved allosteric network.

ACS Spring Meeting 2021

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