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TitleStructure and activation of the human autophagy-initiating ULK1C:PI3KC3-C1 supercomplex.
Journal, issue, pagesNat Struct Mol Biol, Vol. 32, Issue 9, Page 1596-1605, Year 2025
Publish dateMay 29, 2025
AuthorsMinghao Chen / Thanh N Nguyen / Xuefeng Ren / Grace Khuu / Annan S I Cook / Yuanchang Zhao / Ahmet Yildiz / Michael Lazarou / James H Hurley /
PubMed AbstractThe Unc-51-like kinase protein kinase complex (ULK1C) is the most upstream and central player in the initiation of macroautophagy in mammals. Here, we determined the cryo-electron microscopy ...The Unc-51-like kinase protein kinase complex (ULK1C) is the most upstream and central player in the initiation of macroautophagy in mammals. Here, we determined the cryo-electron microscopy structure of the human ULK1C core at amino-acid-level resolution. We also determined a moderate-resolution structure of the ULK1C core in complex with another autophagy core complex, the class III phosphatidylinositol 3-OH kinase complex I (PI3KC3-C1). We show that the two complexes coassemble through extensive contacts between the FIP200 scaffold subunit of ULK1C and the VPS15, ATG14 and BECN1 subunits of PI3KC3-C1. The FIP200:ATG13:ULK1 core of ULK1C undergoes a rearrangement from 2:1:1 to 2:2:2 stoichiometry in the presence of PI3KC3-C1. This suggests a structural mechanism for the initiation of autophagy through formation of a ULK1C:PI3KC3-C1 supercomplex and dimerization of ULK1 on the FIP200 scaffold.
External linksNat Struct Mol Biol / PubMed:40442316 / PubMed Central
MethodsEM (single particle)
Resolution3.26 - 6.84 Å
Structure data

EMDB-41051: Local refinement map (1/3) of the human ULK1 complex core (EMD-40658)
Method: EM (single particle) / Resolution: 3.97 Å

EMDB-41052: Consensus map of the human ULK1 complex core (EMD-40658)
Method: EM (single particle) / Resolution: 4.2 Å

EMDB-41053: Local refinement map (2/3) of the human ULK1 complex core (EMD-40658)
Method: EM (single particle) / Resolution: 3.35 Å

EMDB-41054: Local refinement map (3/3) of the human ULK1 complex core (EMD-40658)
Method: EM (single particle) / Resolution: 5.15 Å

EMDB-41055: Consensus map of the human PI3KC3-C1 complex (EMD-40669)
Method: EM (single particle) / Resolution: 3.96 Å

EMDB-41056: Local refinement map (1/2) of the human PI3KC3-C1 complex (EMD-40669)
Method: EM (single particle) / Resolution: 3.28 Å

EMDB-41057: Local refinement map (2/2) of the human PI3KC3-C1 complex (EMD-40669)
Method: EM (single particle) / Resolution: 3.26 Å

45297

9c82

EMDB-45297, PDB-9c82:
Structure of human ULK1C:PI3KC3-C1 supercomplex
Method: EM (single particle) / Resolution: 6.84 Å

Source
  • homo sapiens (human)
KeywordsIMMUNE SYSTEM / Autophagy / Protein kinase / Lipid kinase / Supercomplex

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