Structural pathway for PI3-kinase regulation by VPS15 in autophagy

Area of Science:

• Molecular Biology
• Structural Biology
• Cell Biology

Background:

• Class III phosphatidylinositol-3 kinase complexes (PI3KC3-C1 and PI3KC3-C2) are crucial for cellular processes like macroautophagy and endosomal maturation.
• Understanding the activation mechanism of PI3KC3-C1, specifically the VPS34 lipid kinase, is essential for deciphering its biological functions.

Purpose of the Study:

• To elucidate the structural pathway of PI3KC3-C1 enzyme activation.
• To provide atomistic detail on how the VPS34 lipid kinase is activated within the complete PI3K complex.

Main Methods:

• Cryo-electron microscopy (cryo-EM) was employed to analyze the structure of PI3KC3-C1.
• Structural analysis focused on the inactive and active conformations of the enzyme complex.

Main Results:

• The inactive conformation of the VPS15 pseudokinase sequesters its N-myristate, stabilizing the inactive state.
• Enzyme activation involves the liberation of N-myristate and the VPS34 lipid kinase catalyzing phosphatidylinositol-3 phosphate production on membranes.
• VPS15 pseudokinase binding to GTP and membrane interactions stabilize interactions that promote activation and autoinhibition release.

Conclusions:

• The study reveals the structural basis for VPS34 lipid kinase activation within the PI3KC3-C1 complex.
• These findings offer detailed insights into the regulation of phosphatidylinositol-3 phosphate production, a key signaling lipid.