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

Author

Listed:
  • 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
    Soochow University)

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.

Suggested Citation

  • Jiangqing Dong & Ximing Du & Huan Wang & Jue Wang & Chang Lu & Xiang Chen & Zhiwen Zhu & Zhipu Luo & Li Yu & Andrew J. Brown & Hongyuan Yang & Jia-Wei Wu, 2019. "Allosteric enhancement of ORP1-mediated cholesterol transport by PI(4,5)P2/PI(3,4)P2," Nature Communications, Nature, vol. 10(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-08791-0
    DOI: 10.1038/s41467-019-08791-0
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    Cited by:

    1. Darshini Jeyasimman & Bilge Ercan & Dennis Dharmawan & Tomoki Naito & Jingbo Sun & Yasunori Saheki, 2021. "PDZD-8 and TEX-2 regulate endosomal PI(4,5)P2 homeostasis via lipid transport to promote embryogenesis in C. elegans," Nature Communications, Nature, vol. 12(1), pages 1-21, December.

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