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

Abstract

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.