Structural pathway for PI3-kinase regulation by VPS15 in autophagy

• DOI: 10.1126/science.adl3787
• Publication Date: 2025-02-06T19:01:26Z
• Authors: Annan S. I. Cook; Minghao Chen; Thanh N. Nguyen; Ainara Claveras C...; Grace Khuu; Shanlin Rao; Samantha N. Garcia; Mingxuan Yang; Anthony T. Iavarone; Xuefeng Ren; Michael Lazarou; Gerhard Hummer; James H. Hurley

The class III phosphatidylinositol-3 kinase complexes I and II (PI3KC3-C1 -C2) have vital roles in macroautophagy endosomal maturation, respectively. We elucidated a structural pathway of enzyme activation through cryo-EM analysis PI3KC3-C1. inactive conformation the VPS15 pseudokinase stabilizes conformation, sequestering its N -myristate N-lobe pseudokinase. Upon activation, myristate is liberated such that VPS34 lipid catalyzes PI3P production on membranes. domain binds tightly to guanosine triphosphate (GTP), web interactions autoinhibit cytosolic complex promote upon membrane binding. These findings show atomistic detail how activated context complete PI3K complex.