The lipid kinase VPS34 orchestrates diverse processes, including autophagy, endocytic sorting, phagocytosis, anabolic responses and cell division. VPS34 forms various complexes that help adapt it to specific pathways, with complexes I and II being the most prominent ones. We found that physicochemical properties of membranes strongly modulate VPS34 activity. Greater unsaturation of both substrate and non-substrate lipids, negative charge and curvature activate VPS34 complexes, adapting them to their cellular compartments. Hydrogen/deuterium exchange mass spectrometry (HDX-MS) of complexes I and II on membranes elucidated structural determinants that enable them to bind membranes. Among these are the Barkor/ATG14L autophagosome targeting sequence (BATS), which makes autophagy-specific complex I more active than the endocytic complex II, and the Beclin1 BARA domain. Interestingly, even though Beclin1 BARA is common to both complexes, its membrane-interacting loops are critical for complex II, but have only a minor role for complex I.

中文翻译：

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膜特性调节内体和自噬人 VPS34 复合物的活性

脂质激酶 VPS34 协调多种过程，包括自噬、内吞分选、吞噬作用、合成代谢反应和细胞分裂。VPS34 形成各种复合物，有助于使其适应特定的途径，其中复合物 I 和 II 是最突出的。我们发现膜的物理化学性质强烈调节 VPS34 活性。底物和非底物脂质的更大不饱和度、负电荷和曲率激活 VPS34 复合物，使其适应其细胞区室。膜上复合物 I 和 II 的氢/氘交换质谱 (HDX-MS) 阐明了使它们能够结合膜的结构决定因素。其中包括 Barkor/ATG14L 自噬体靶向序列 (BATS)，它使自噬特异性复合物 I 比内吞复合物 II 更活跃，和 Beclin1 BARA 域。有趣的是，尽管 Beclin1 BARA 对两种复合物都很常见，但它的膜相互作用环对复合物 II 至关重要，但对复合物 I 的作用很小。