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

Jiangqing Dong, Ximing Du, Huan Wang, Jue Wang, Chang Lu, Xiang Chen, Zhiwen Zhu, Zhipu Luo, Li Yu, Andrew J. Brown, Hongyuan Yang () and Jia-Wei Wu ()
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Jiangqing Dong: Tsinghua University
Ximing Du: the University of New South Wales
Huan Wang: Tsinghua University
Jue Wang: Soochow University
Chang Lu: Tsinghua University
Xiang Chen: Tsinghua University
Zhiwen Zhu: Tsinghua University
Zhipu Luo: Soochow University
Li Yu: Tsinghua University
Andrew J. Brown: the University of New South Wales
Hongyuan Yang: the University of New South Wales
Jia-Wei Wu: Tsinghua University

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: 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)P2- or PI(3,4)P2-dependent cholesterol transporter, but cannot transport any PIPs. In cells, both ORP1L and PI(3,4)P2 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)P2 display open conformations essential for ORP function. PI(4,5)P2/PI(3,4)P2 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.

Date: 2019
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DOI: 10.1038/s41467-019-08791-0

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