9MHF

Cryo-EM reconstruction of PI3KC3-C1 in complex with Human RAB1A(Q70L)

9MHF の概要

• エントリーDOI: 10.2210/pdb9mhf/pdb
• EMDBエントリー: 48276
• 分子名称: Phosphoinositide 3-kinase regulatory subunit 4, Phosphatidylinositol 3-kinase catalytic subunit type 3, Beclin 1-associated autophagy-related key regulator, ... (9 entities in total)
• 機能のキーワード: complex, gtpase, gtp-binding, autophagy, kinase, lipid kinase, signaling protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 394359.08

構造登録者

Cook, A.S.I.,Hurley, J.H.,Chen, M. (登録日: 2024-12-11, 公開日: 2025-02-12, 最終更新日: 2025-09-03)

主引用文献

Cook, A.S.I.,Chen, M.,Nguyen, T.N.,Cabezudo, A.C.,Khuu, G.,Rao, S.,Garcia, S.N.,Yang, M.,Iavarone, A.T.,Ren, X.,Lazarou, M.,Hummer, G.,Hurley, J.H.
Structural pathway for PI3-kinase regulation by VPS15 in autophagy.
Science, 388:eadl3787-eadl3787, 2025

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

PubMed: 39913640
DOI: 10.1126/science.adl3787

実験手法

ELECTRON MICROSCOPY (2.73 Å)