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| Title | A GABARAP-PtdIns3K-C1 positive feedback loop at the heart of the phagophore nucleation. |
|---|---|
| Journal, issue, pages | Nat Commun, Vol. 17, Issue 1, Year 2026 |
| Publish date | Jul 30, 2026 |
Authors | Antoine N Dessus / Yohei Ohashi / Maxime Bourguet / Tomos E Morgan / Anastasia Nunez / Maria Manifava / Nicholas T Ktistakis / Roger L Williams / ![]() |
| PubMed Abstract | In mammalian cells, autophagosomes can reach diameters of over 1000 nm within 30 min after triggering starvation, but how such substantial amounts of membranes can be synthesized remains elusive. ...In mammalian cells, autophagosomes can reach diameters of over 1000 nm within 30 min after triggering starvation, but how such substantial amounts of membranes can be synthesized remains elusive. The phagophore initiation needs the lipid kinase PIK3C3-Complex 1 (PtdIns3K-C1), which produces phosphatidylinositol-3-phosphate (PtdIns3P). PtdIns3P recruits WIPI2 that facilitates lipidation of mammalian ATG8 (mATG8) family proteins on phagophores. Here we show that recombinant membrane-coupled GABARAP binds to and potently activates PtdIns3K-C1. By a combination of cryo-electron microscopy, structural mass spectrometry, activity assays and mutagenesis, we show that GABARAP activates PtdIns3K-C1 through two binding sites. We propose that once GABARAP is indirectly recruited by PtdIns3P generated by basal activity of PtdIns3K-C1, a positive feedback loop is formed where PtdIns3K-C1 interacts with GABARAP and becomes activated to produce more PtdIns3P, thereby further stimulating GABARAP lipidation. This mechanism would be central for autophagosome biogenesis, where enlarged membranes need to be rapidly synthesized. |
External links | Nat Commun / PubMed:42693081 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 3.28 - 4.01 Å |
| Structure data | ![]() EMDB-56343: Cryo-EM structure of human VPS34-CI in complex with GABARAP - alternative conformation, local refinement on BECLIN1 and ATG14L C-terminal domains. ![]() EMDB-56345: Cryo-EM structure of human VPS34-CI in complex with GABARAP - alternative conformation, consensus map ![]() EMDB-56346: Cryo-EM structure of human VPS34-CI in complex with GABARAP, consensus map ![]() EMDB-56347: Cryo-EM structure of human VPS34-CI in complex with GABARAP, local refinement on VPS34 and VPS15 kinase domains. ![]() EMDB-56348: Cryo-EM structure of human VPS34-CI in complex with GABARAP, local refinement on the core of VPS34-CI. ![]() EMDB-56350: Cryo-EM structure of human VPS34-CI in complex with GABARAP, local refinement on VPS15 helical solenoid, and BECLIN1 and ATG14L N-terminal domains. ![]() EMDB-56351: Cryo-EM structure of human VPS34-CI in complex with GABARAP, local refinement on GABARAP. ![]() EMDB-56353: Cryo-EM structure of human VPS34-CI in complex with GABARAP, local refinement on BECLIN1 and ATG14L C-terminal domains. EMDB-56357: Cryo-EM structure of human VPS34-CI in complex with GABARAP, composite map EMDB-56358: Cryo-EM structure of human VPS34-CI in complex with GABARAP - alternative conformation, composite map ![]() EMDB-56454: Cryo-EM structure of human VPS34-CI with ADP:MgF3 - consensus map ![]() EMDB-56455: Cryo-EM structure of human VPS34-CI with ADP:MgF3 - local refinement on the complex base ![]() EMDB-56456: Cryo-EM structure of human VPS34-CI with ADP:MgF3 - local refinement on VPS34 and VPS15 kinases ![]() EMDB-56457: Cryo-EM structure of human VPS34-CI with ADP:MgF3 - local refinement on ATG14L and BECLIN1 C-termini EMDB-56458: Cryo-EM structure of human VPS34-CI with ADP:MgF3 - composite map |
| Chemicals | ![]() ChemComp-MYR: ![]() ChemComp-GDP: ![]() ChemComp-MG: ![]() ChemComp-ZN: ![]() ChemComp-ADP: |
| Source |
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Keywords | LIPID BINDING PROTEIN / Lipid kinase / Complex / Autophagy |
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homo sapiens (human)
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