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

Chen, M; Nguyen, TN; Ren, X; Khuu, G; Cook, ASI; Zhao, Y; Yildiz, A; Lazarou, M; Hurley, JH

Author(s): Chen, M; Nguyen, TN; Ren, X; Khuu, G; Cook, ASI; Zhao, Y; Yildiz, A; Lazarou, M; Hurley, JH;
Details: Publication Year 2025-09,Volume 32,Issue #9,Page 1596-1605
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
Keywords: Humans; *Autophagy-Related Protein-1 Homolog/chemistry/metabolism/ultrastructure; *Autophagy; Cryoelectron Microscopy; *Class III Phosphatidylinositol 3-Kinases/chemistry/metabolism/ultrastructure; Autophagy-Related Proteins/metabolism/chemistry; *Intracellular Signaling Peptides and Proteins/chemistry/metabolism; Models, Molecular; Beclin-1/metabolism/chemistry; Protein Binding; Adaptor Proteins, Vesicular Transport
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: 2025-09-23 11:10:33