2. Academic Validation
  3. ORP2 Delivers Cholesterol to the Plasma Membrane in Exchange for Phosphatidylinositol 4, 5-Bisphosphate (PI(4,5)P2)

ORP2 Delivers Cholesterol to the Plasma Membrane in Exchange for Phosphatidylinositol 4, 5-Bisphosphate (PI(4,5)P2)

  • Mol Cell. 2019 Feb 7;73(3):458-473.e7. doi: 10.1016/j.molcel.2018.11.014.
Huan Wang 1,  Qianli Ma 2,  Yanfei Qi 2,  Jiangqing Dong 1,  Ximing Du 2,  James Rae 3,  Jue Wang 4,  Wei-Feng Wu 4,  Andrew J Brown 2,  Robert G Parton 3,  Jia-Wei Wu 5,  Hongyuan Yang 6
Affiliations

Affiliations

  • 1 Beijing Advanced Innovation Center for Structural Biology, MOE Key Laboratory for Protein Science, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
  • 2 School of Biotechnology and Biomolecular Sciences, the University of New South Wales, Sydney, NSW 2052, Australia.
  • 3 Center for Microscopy and Microanalysis, Institute of Molecular Bioscience, the University of Queensland, St. Lucia, 4072 QLD, Australia.
  • 4 Institute of Molecular Enzymology, Soochow University, Suzhou, Jiangsu 215123, China.
  • 5 Beijing Advanced Innovation Center for Structural Biology, MOE Key Laboratory for Protein Science, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China; Institute of Molecular Enzymology, Soochow University, Suzhou, Jiangsu 215123, China. Electronic address: jiaweiwu@mail.tsinghua.edu.cn.
  • 6 School of Biotechnology and Biomolecular Sciences, the University of New South Wales, Sydney, NSW 2052, Australia. Electronic address: h.rob.yang@unsw.edu.au.
PMID: 30581148 DOI: 10.1016/j.molcel.2018.11.014
Abstract

Cholesterol is highly enriched at the plasma membrane (PM), and lipid transfer proteins may deliver Cholesterol to the PM in a nonvesicular manner. Here, through a mini-screen, we identified the oxysterol binding protein (OSBP)-related protein 2 (ORP2) as a novel mediator of selective Cholesterol delivery to the PM. Interestingly, ORP2-mediated enrichment of PM Cholesterol was coupled with the removal of phosphatidylinositol 4, 5-bisphosphate (PI(4,5)P2) from the PM. ORP2 overexpression or deficiency impacted the levels of PM Cholesterol and PI(4,5)P2, and ORP2 efficiently transferred both Cholesterol and PI(4,5)P2in vitro. We determined the structure of ORP2 in complex with PI(4,5)P2 at 2.7 Å resolution. ORP2 formed a stable tetramer in the presence of PI(4,5)P2, and tetramerization was required for ORP2 to transfer PI(4,5)P2. Our results identify a novel pathway for Cholesterol delivery to the PM and establish ORP2 as a key regulator of both Cholesterol and PI(4,5)P2 of the PM.

Keywords

OCRL; ORP1; ORP5; OSBP; PI(4,5)P(2); PI4P; cholesterol; membrane contact sites; oxysterol binding protein; phosphoinositides.

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