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PreprintCited by 40Autophagy in Disease and TherapyUbiquitin and proteasome pathwaysCellular transport and secretion

The DOI matches its Crossref record; 1 of the 1 references it cites were found in a registry or an index.

Structure and activation of the human autophagy-initiating ULK1C:PI3KC3-C1 supercomplex

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Chen, Minghao, Nguyen, Thanh N., Ren, Xuefeng, Khuu, Grace, Cook, Annan S. I., Zhao, Yuanchang, Yildiz, Ahmet, Lazarou, Michael, Hurley, James H.·2023·Nature Structural & Molecular Biology
DOI 10.1101/2023.06.01.543278PMC PMC12440827

Preprint — published as 10.1038/s41594-025-01557-x

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Abstract

The unc-51-like kinase protein kinase complex (ULK1C) is the most upstream and central player in the initiation of macroautophagy in mammals. Here, the cryo-EM structure of the human ULK1C core was determined at amino acid residue-level resolution. A moderate resolution structure of the ULK1C core in complex with another autophagy core complex, the class III phosphatidylinositol 3-kinase complex I (PI3KC3-C1) was also determined. The two complexes co-assemble 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.

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Metadata

Authors
Chen, M., Nguyen, T. N., Ren, X., Khuu, G., Cook, A. S. I., Zhao, Y., Yildiz, A., Lazarou, M., & Hurley, J. H.
Affiliations
  • QB3 (US)
  • The University of Melbourne (AU)
  • University of California, Berkeley (US)
Corresponding author
Hurley, James H.
ORCID
Venue
Nature Structural & Molecular Biology
Publisher
openRxiv
Published
2023-06-01
Volume
32
Issue
9
Pages
1596-1605
ISSN
1545-9985 (ISSN-L)
DOI
10.1101/2023.06.01.543278
PMC
PMC12440827
OpenAlex
W4410866776
Cited by
40
References
1
Citations by year
2026: 18 · 2025: 15 · 2024: 5 · 2023: 2
FWCI
22.69
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Structural & Molecular Biology (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • Minerva Access (University of Melbourne) (submittedVersion, cc-by)
Funders
  • Michael J. Fox Foundation for Parkinson's Research (ASAP-000350)
  • National Institutes of Health
  • National Institute of General Medical Sciences (T32GM008295, R35GM136414)
  • National Institute of Neurological Disorders and Stroke (R01NS134598)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
Keywords
autophagy initiation, macroautophagy, FIP200, ATG13, VPS15, Beclin-1, ATG14, protein complex structure, cryo-EM structure
MeSH terms
Autophagy-Related Proteins, Beclin-1, Autophagy-Related Protein-1 Homolog, Autophagy, Humans, Models, Molecular, Protein Binding, Cryoelectron Microscopy, Adaptor Proteins, Vesicular Transport, Intracellular Signaling Peptides and Proteins, Class III Phosphatidylinositol 3-Kinases

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