9MHG

Cryo EM reconstruction of PI3KC3-C1 in complex with Human RAB1A(Q70L), VPS34 kinase domain in the inactive conformation

Summary for 9MHG

• Entry DOI: 10.2210/pdb9mhg/pdb
• EMDB information: 48277
• Descriptor: Phosphoinositide 3-kinase regulatory subunit 4, Phosphatidylinositol 3-kinase catalytic subunit type 3, Beclin 1-associated autophagy-related key regulator, ... (8 entities in total)
• Functional Keywords: complex, gtpase, gtp-binding, autophagy, kinase, lipid kinase, signaling protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 394359.08

Authors

Cook, A.S.I.,Hurley, J.H.,Chen, M. (deposition date: 2024-12-11, release date: 2025-02-12, Last modification date: 2025-09-03)

Primary citation

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

Experimental method

ELECTRON MICROSCOPY (3.2 Å)