Structure and activation of the human autophagy-initiating ULK1C:PI3KC3-C1 supercomplex
- Author(s)
- Chen, M; Nguyen, TN; Ren, X; Khuu, G; Cook, ASI; Zhao, Y; Yildiz, A; Lazarou, M; Hurley, JH;
- Journal Title
- Nature Structural & Molecular Biology
- 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.
- Publisher
- Springer Nature
- Research Division(s)
- Ubiquitin Signalling
- PubMed ID
- 40442316
- Publisher's Version
- https://doi.org/10.1038/s41594-025-01557-x
- Open Access at Publisher's Site
https://doi.org/10.1038/s41594-025-01557-x.- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2025-06-26 09:55:13
Last Modified: 2025-06-26 09:56:13