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

被引:62
作者
Dong, Jiangqing [1 ]
Du, Ximing [2 ]
Wang, Huan [1 ]
Wang, Jue [3 ]
Lu, Chang [1 ]
Chen, Xiang [1 ]
Zhu, Zhiwen [1 ]
Luo, Zhipu [3 ]
Yu, Li [1 ]
Brown, Andrew J. [2 ]
Yang, Hongyuan [2 ]
Wu, Jia-Wei [1 ,3 ]
机构
[1] Tsinghua Univ, Beijing Adv Innovat Ctr Struct Biol, Sch Life Sci, Tsinghua Peking Ctr Life Sci,MOE Key Lab Prot Sci, Beijing 100084, Peoples R China
[2] Univ New South Wales, Sch Biotechnol & Biomol Sci, Sydney, NSW 2052, Australia
[3] Soochow Univ, Inst Mol Enzymol, Suzhou 215123, Jiangsu, Peoples R China
基金
澳大利亚国家健康与医学研究理事会; 国家重点研发计划; 英国医学研究理事会; 中国国家自然科学基金;
关键词
OXYSTEROL-BINDING PROTEIN; CONTACT SITES; STEROL; ER; REVEALS; MTORC1; VAP; TRAFFICKING; DYNAMICS; DRIVEN;
D O I
10.1038/s41467-019-08791-0
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页数:16
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