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

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.

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