Allosteric enhancement of ORP1-mediated cholesterol transport by PI(4,5)P2/PI(3,4)P2

作者：Jiangqing Dong, Ximing Du, Huan Wang, Jue Wang, Chang Lu, Xiang Chen, Zhiwen Zhu, Zhipu Luo, Li Yu, Andrew J. Brown, Hongyuan Yang, Jiawei Wu · 发表于：Nature Communications · 年份：2019 · DOI：10.1038/s41467-019-08791-0 · 被引用次数：98 · 研究领域：Cellular transport and secretion、Lipid Membrane Structure and Behavior、Autophagy in Disease and Therapy

Abstract Phosphatidylinositol phosphates (PIPs) and cholesterol are known to regulate the function of late endosomes and lysosomes (LELs), and ORP1L specifically localizes to LELs. Here, we show in vitro that ORP1 is a PI(4,5)P 2 - or PI(3,4)P 2 -dependent cholesterol transporter, but cannot transport any PIPs. In cells, both ORP1L and PI(3,4)P 2 are required for the efficient removal of cholesterol from LELs. Structures of the lipid-binding domain of ORP1 (ORP1-ORD) in complex with cholesterol or PI(4,5)P 2 display open conformations essential for ORP function. PI(4,5)P 2 /PI(3,4)P 2 can facilitate ORP1-mediated cholesterol transport by promoting membrane targeting and cholesterol extraction. Thus, our work unveils a distinct mechanism by which PIPs may allosterically enhance OSBP/ORPs-mediated transport of major lipid species such as cholesterol.