VPS15在自噬中调控pi3激酶的结构途径

IF 45.8 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Pub Date : 2025-02-06 DOI:10.1126/science.adl3787

Annan S. I. Cook, Minghao Chen, Thanh N. Nguyen, Ainara Claveras Cabezudo, Grace Khuu, Shanlin Rao, Samantha N. Garcia, Mingxuan Yang, Anthony T. Iavarone, Xuefeng Ren, Michael Lazarou, Gerhard Hummer, James H. Hurley

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引用次数: 0

摘要

III类磷脂酰肌醇-3激酶复合物I和II （PI3KC3-C1和-C2）分别在巨噬和内体成熟中起重要作用。我们通过低温电镜分析阐明了PI3KC3-C1酶活化的结构途径。VPS15伪激酶的非活性构象稳定了非活性构象，将其肉豆蔻酸酯隔离在伪激酶的N叶中。激活后，肉豆蔻酸酯被释放，使VPS34脂质激酶催化膜上PI3P的产生。VPS15伪激酶结构域与鸟苷三磷酸（GTP）紧密结合，并稳定相互作用网络，自抑制胞质复合物并促进膜结合时的激活。这些发现在原子细节上显示了VPS34脂质激酶是如何在一个完整的PI3K复合物的背景下被激活的。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Structural pathway for PI3-kinase regulation by VPS15 in autophagy

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Structural pathway for PI3-kinase regulation by VPS15 in autophagy

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 N-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.

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来源期刊

Science 综合性期刊-综合性期刊

CiteScore

61.10

自引率

0.90%

发文量

审稿时长

2.1 months

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