Molecular basis for Gβγ-mediated activation of phosphoinositide 3-kinase γ.

ABSTRACT: The conversion of PIP2 to PIP3 by phosphoinositide 3-kinase γ (PI3Kγ) is a critical step in neutrophil chemotaxis and is essential for metastasis in many types of cancer. PI3Kγ is activated via directed interaction with Gβγ heterodimers released from cell-surface G protein-coupled receptors (GPCRs) responding to extracellular signals. To resolve how Gβγ activates PI3Kγ, we determined cryo-EM reconstructions of PI3Kγ-Gβγ complexes in the presence of various substrates/analogs, revealing two distinct Gβγ binding sites, one on the p110γ helical domain and one on the C-terminal domain of the p101 subunit. Comparison of these complexes with structures of PI3Kγ alone demonstrates conformational changes in the kinase domain upon Gβγ binding similar to those induced by Ras·GTP. Assays of variants

SUBMITTER: Chen CL 

PROVIDER: S-EPMC10187307 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature