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

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.

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Publication Details

Journal
Nature Structural & Molecular Biology
Published
2025-05-29
DOI
https://doi.org/10.1038/s41594-025-01557-x
Citations
13
Primary Topic
Autophagy in Disease and Therapy
Type
article
Field-Weighted Citation Impact
17.60

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article

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

Minghao Chen, Yuanchang Zhao, Thanh Ngoc Nguyen, Xuefeng Ren et al.
13 citations
Nature Structural & Molecular Biology
Autophagy in Disease and Therapy
17.60
article

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

Minghao Chen, Yuanchang Zhao, Thanh Ngoc Nguyen, Xuefeng Ren, Annan SI Cook, James H. Hurley, Michael Lazarou, Grace Khuu, Ahmet Yıldız
article en
13 citations

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, 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.

Nature Structural & Molecular BiologyVol. 32(9)
QB3 (US), The University of Melbourne (AU), Walter and Eliza Hall Institute of Medical Research (AU), Australian Regenerative Medicine Institute (AU), Research Network (United States) (US), Monash University (AU), University of California, Berkeley (US)
National Institutes of Health
Openalex Percentile: Top 1%
Autophagy in Disease and Therapy
17.60
DOIOpen Access PDFOpenAlex
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Structure and activation of the human autophagy-initiating ULK1C:PI3KC3-C1 supercomplex — Minghao Chen, Yuanchang Zhao, et al. · Nature Structural & Molecular Biology (2025) | TGRS Research Map | TGRS