Structural pathway for PI3-kinase regulation by VPS15 in autophagy

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 <i>N</i>-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.

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Publication Details

Journal
Science
Published
2025-02-06
DOI
https://doi.org/10.1126/science.adl3787
Citations
25
Primary Topic
Autophagy in Disease and Therapy
Type
article
Field-Weighted Citation Impact
33.85
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article

Structural pathway for PI3-kinase regulation by VPS15 in autophagy

Ainara Claveras Cabezudo, Minghao Chen, Anthony T. Iavarone, Thanh Ngoc Nguyen et al.
25 citations
Science
Autophagy in Disease and Therapy
33.85
article

Structural pathway for PI3-kinase regulation by VPS15 in autophagy

Ainara Claveras Cabezudo, Minghao Chen, Anthony T. Iavarone, Thanh Ngoc Nguyen, Shanlin Rao, Xuefeng Ren, Annan SI Cook, Gerhard Hummer, James H. Hurley, Michael Lazarou, Grace Khuu, Samantha N. Garcia, M. Yang
article en
25 citations

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 <i>N</i>-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.

ScienceVol. 388(6743)
QB3 (US), Goethe University Frankfurt (DE), The University of Melbourne (AU), Walter and Eliza Hall Institute of Medical Research (AU), Australian Regenerative Medicine Institute (AU), Max Planck Institute of Biophysics (DE), Research Network (United States) (US), Monash University (AU), University of California, Berkeley (US)
Clean water and sanitation
Openalex Percentile: Top 0%
Autophagy in Disease and Therapy
33.85
DOIOpen Access PDFOpenAlex
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