Structural pathway for PI3-kinase regulation by VPS15 in autophagy
Open accessPublished version of a preprint
Abstract
The class III phosphatidylinositol-3 kinase complexes I and II (PI3KC3-C1 and -C2) have vital roles in macroautophagy and endosomal maturation, respectively. We elucidated a structural pathway of enzyme activation through cryo-EM analysis of PI3KC3-C1. The inactive conformation of the VPS15 pseudokinase stabilizes the inactive conformation, sequestering its N -myristate in the N-lobe of the pseudokinase. Upon activation, the myristate is liberated such that the VPS34 lipid kinase catalyzes PI3P production on membranes. The VPS15 pseudokinase domain binds tightly to guanosine triphosphate (GTP), and stabilizes a web of interactions to autoinhibit the cytosolic complex and to promote the 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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- Authors
- 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.
- Affiliations
- QB3 (US)
- The University of Melbourne (AU)
- Max Planck Institute of Biophysics (DE)
- University of California, Berkeley (US)
- Goethe University Frankfurt (DE)
- Corresponding author
- Cook, Annan S. I.
- Chen, Minghao
- Nguyen, Thanh N.
- Cabezudo, Ainara Claveras
- Lazarou, Michael
- Hummer, Gerhard
- Hurley, James H.
- ORCID
- Venue
- Science
- Published
- 2025-02-06
- Volume
- 388
- Issue
- 6743
- Pages
- eadl3787-eadl3787
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC11985297
- OpenAlex
- W4407199655
- Cited by
- 34
- References
- 9
- Citations by year
- 2026: 16 · 2025: 16 · 2024: 1 · 2023: 1
- FWCI
- 22.18
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Science (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Minerva Access (University of Melbourne) (submittedVersion, cc-by)
- Funders
- Michael J. Fox Foundation for Parkinson's Research (ASAP-000350)
- Max-Planck-Gesellschaft
- National Institutes of Health (1s10od020062-01)
- National Institute of Neurological Disorders and Stroke (R01NS134598)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- class III phosphatidylinositol 3-kinase, autophagy, endosomal maturation, enzyme activation, myristate, GTP binding, autoinhibition, membrane binding, cryo-EM structure
- MeSH terms
- Protein Domains, Animals, Autophagy, Enzyme Activation, Humans, Protein Conformation, Phosphatidylinositol Phosphates, Cryoelectron Microscopy, Class III Phosphatidylinositol 3-Kinases, Vacuolar Sorting Protein VPS15
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