研究人员表示，III类磷脂酰肌醇-3激酶复合物I和II（PI3KC3-C1和- C2）分别在巨自噬和内体成熟中发挥重要作用。
研究人员通过冷冻电镜分析PI3KC3-C1阐明了酶激活的结构路径。VPS15伪激酶的非活性构象稳定了非活性状态，将其N-肉豆蔻酸酯固定在伪激酶的N叶片中。在激活后，肉豆蔻酸酯被释放，使得VPS34脂质激酶能够在膜上催化PI3P的生成。VPS15伪激酶结构域与三磷酸鸟苷（GTP）紧密结合，稳定了一系列相互作用，从而自我抑制细胞质复合物，并在膜结合后促进激活。
这些发现详细展示了VPS34脂质激酶如何在完整PI3K复合物的背景下被激活。
附：英文原文
Title: Structural pathway for PI3-kinase regulation by VPS15 in autophagy
Author: 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
Issue&Volume: 2025-02-06
Abstract: The class III phosphatidylinositol-3 kinase complexes I and II (PI3KC3-C1 and -C2) have vital roles in macroautophagy and endosomal maturation, respectively. We elucidated a structural pathway of enzyme activation through cryo-EM 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 PI3P production on membranes. The VPS15 pseudokinase domain binds tightly to guanosine triphosphate (GTP), and stabilizes a web of interactions to autoinhibit the cytosolic complex and to promote the 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.
DOI: adl3787
Source: https://www.science.org/doi/10.1126/science.adl3787