9ni6
Cryo-EM structure of the Class 1 PI3K alpha/KRas complex on POPC/POPS nanodiscs
Structural highlights
FunctionP85A_HUMAN Binds to activated (phosphorylated) protein-Tyr kinases, through its SH2 domain, and acts as an adapter, mediating the association of the p110 catalytic unit to the plasma membrane. Necessary for the insulin-stimulated increase in glucose uptake and glycogen synthesis in insulin-sensitive tissues. Plays an important role in signaling in response to FGFR1, FGFR2, FGFR3, FGFR4, KITLG/SCF, KIT, PDGFRA and PDGFRB. Likewise, plays a role in ITGB2 signaling.[1] [2] [3] Publication Abstract from PubMedPI3Kalpha is a potent oncogene that converts PIP2 to PIP3 at the plasma membrane upon activation by receptor tyrosine kinases and Ras GTPases. In the absence of any structures of activated PI3Kalpha, the molecular details of its activation remain unknown. Here, we present cryo-EM structures of the PI3Kalpha/KRas complex embedded in lipid nanodiscs, revealing a rich ensemble of PI3Kalpha states adopted at the membrane surface. The sequential addition of a lipid bilayer, PIP2 and an activating phosphopeptide leads to the progressive release of key inhibitory domains from the PI3Kalpha catalytic core, which directly correlates with the reorganization of its active site. While association with POPC/POPS nanodiscs partially relieves PI3Kalpha autoinhibition, incorporation of PIP2 triggers near-complete displacement of PI3Kalpha inhibitory domains and significant restructuring of active site regulatory motifs. The addition of the activating phosphopeptide induces dimerization of the PI3Kalpha/KRas complex through a p110alpha catalytic subunit-mediated interface that is sterically occluded in autoinhibited PI3Kalpha. In cells, this dimeric PI3Kalpha complex amplifies Akt signaling in response to growth factor stimulation. Collectively, our structures map the conformational landscape of PI3Kalpha activation and reveal previously unexplored interfaces for potential therapeutic targeting. Structures of the PI3Kalpha/KRas complex on lipid bilayers reveal the molecular mechanism of PI3Kalpha activation.,Torosyan H, Paul MD, Maker A, Meyer BG, Jura N, Verba KA bioRxiv [Preprint]. 2025 Mar 25:2025.03.22.644753. doi: , 10.1101/2025.03.22.644753. PMID:40196507[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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