自噬过程中VPS15对PI3激酶调节的结构途径。
Structural pathway for PI3-kinase regulation by VPS15 in autophagy.
作者信息
Cook Annan S I, Chen Minghao, Nguyen Thanh N, Cabezudo Ainara Claveras, Khuu Grace, Rao Shanlin, Garcia Samantha N, Yang Mingxuan, Iavarone Anthony T, Ren Xuefeng, Lazarou Michael, Hummer Gerhard, Hurley James H
机构信息
Graduate Group in Biophysics, University of California, Berkeley, Berkeley, CA, USA.
California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA, USA.
出版信息
Science. 2025 Apr 11;388(6743):eadl3787. doi: 10.1126/science.adl3787.
The class III phosphatidylinositol-3 kinase complexes I and II (PI3KC3-C1 and PI3KC3-C2) have vital roles in macroautophagy and endosomal maturation, respectively. We elucidated a structural pathway of enzyme activation through cryo-electron microscopy analysis of PI3KC3-C1. The inactive conformation of the VPS15 pseudokinase stabilizes the inactive conformation, sequestering its -myristate in the N-lobe of the pseudokinase. Upon activation, the myristate is liberated such that the VPS34 lipid kinase catalyzes phosphatidylinositol-3 phosphate production on membranes. The VPS15 pseudokinase domain binds tightly to guanosine triphosphate and stabilizes a web of interactions to autoinhibit the cytosolic complex and promote activation upon membrane binding. These findings show in atomistic detail how the VPS34 lipid kinase is activated in the context of a complete PI3K complex.
III类磷脂酰肌醇-3激酶复合物I和II（PI3KC3-C1和PI3KC3-C2）分别在巨自噬和内体成熟过程中发挥着至关重要的作用。我们通过对PI3KC3-C1进行冷冻电子显微镜分析，阐明了一条酶激活的结构途径。VPS15假激酶的无活性构象稳定了无活性构象，将其肉豆蔻酸酯隔离在假激酶的N叶中。激活后，肉豆蔻酸酯被释放，使得VPS34脂质激酶催化膜上磷脂酰肌醇-3-磷酸的产生。VPS15假激酶结构域与三磷酸鸟苷紧密结合，并稳定相互作用网络以自抑制胞质复合物，并在膜结合时促进激活。这些发现以原子细节展示了VPS34脂质激酶在完整PI3K复合物的背景下是如何被激活的。
Zotero 插件