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)
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ORP2 将胆固醇传递至质膜，以交换磷脂酰肌醇 4, 5-二磷酸 (PI(4,5)P2)
DOI：
10.1016/j.molcel.2018.11.014
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发表时间：
2019-02-07
期刊：
影响因子：
16
通讯作者：
Yang, Hongyuan
中科院分区：
文献类型：
--
作者：
Wang, Huan;Ma, Qianli;Yang, Hongyuan
胆固醇在质膜上高度浓缩，脂转移蛋白可能以非囊泡的方式将胆固醇输送到质膜。在这里，通过一个小屏幕，我们确定了氧固醇结合蛋白(OSBP)相关蛋白2(ORP2)是一种选择性地将胆固醇输送到PM的新介质有趣的是，ORP2介导的PM胆固醇的浓缩与PM中磷脂酰肌醇4，5-二磷酸(PI(4，5)P-2)的去除是耦合的ORP2过表达或缺失影响PM胆固醇和PI(4，5)P-2的水平，ORP2在体外有效地转移胆固醇和PI(4，5)P-2。在2.7埃分辨率下，我们确定了ORP2与PI(4，5)P-2的配合物的结构。在PI(4，5)P-2存在下，ORP2形成稳定的四聚体，ORP2需要四聚反应才能转移PI(4，5)P-2。我们的结果确定了一条新的胆固醇传递到PM的途径，并建立了ORP2作为PM的胆固醇和PI(4，5)P-2的关键调节因子
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)P-2) from the PM. ORP2 overexpression or deficiency impacted the levels of PM cholesterol and PI(4,5)P-2, and ORP2 efficiently transferred both cholesterol and PI(4,5)P-2 in vitro. We determined the structure of ORP2 in complex with PI(4,5)P-2 at 2.7 angstrom resolution. ORP2 formed a stable tetramer in the presence of PI(4,5)P-2, and tetramerization was required for ORP2 to transfer PI(4,5)P-2. 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) P-2 of the PM.