人类自噬起始ULK1C:PI3KC3-C1超复合物的结构与激活
Structure and activation of the human autophagy-initiating ULK1C:PI3KC3-C1 supercomplex.
作者信息
Chen Minghao, Nguyen Thanh N, Ren Xuefeng, Khuu Grace, Cook Annan S I, Zhao Yuanchang, Yildiz Ahmet, Lazarou Michael, Hurley James H
机构信息
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA.
California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA, USA.
出版信息
Nat Struct Mol Biol. 2025 May 29. doi: 10.1038/s41594-025-01557-x.
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.
Unc-51样激酶蛋白激酶复合物（ULK1C）是哺乳动物中自噬起始过程中最上游且核心的参与者。在此，我们确定了人类ULK1C核心在氨基酸水平分辨率下的冷冻电镜结构。我们还确定了ULK1C核心与另一个自噬核心复合物III类磷脂酰肌醇3-羟基激酶复合物I（PI3KC3-C1）形成的复合物的中等分辨率结构。我们发现这两个复合物通过ULK1C的FIP200支架亚基与PI3KC3-C1的VPS15、ATG14和BECN1亚基之间的广泛接触而共同组装。在PI3KC3-C1存在的情况下，ULK1C的FIP200:ATG13:ULK1核心的化学计量比从2:1:1重排为2:2:2。这表明了一种通过形成ULK1C:PI3KC3-C1超复合物以及ULK1在FIP200支架上二聚化来启动自噬的结构机制。
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