A Four-Step Cycle Driven by PI(4)P Hydrolysis Directs Sterol/PI(4)P Exchange by the ER-Golgi Tether OSBP
A Four-Step Cycle Driven by PI(4)P Hydrolysis Directs Sterol/PI(4)P Exchange by the ER-Golgi Tether OSBP
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DOI：
10.1016/j.cell.2013.09.056
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发表时间：
2013-11-07
期刊：
影响因子：
64.5
通讯作者：
Antonny, Bruno
中科院分区：
文献类型：
--
作者：
Mesmin, Bruno;Bigay, Joelle;Antonny, Bruno
内质网（ER）-高尔基体膜接触位点的几种蛋白质含有与高尔基体磷酸肌醇PI（4）P相互作用的PH结构域、与ER蛋白VAP-A相互作用的FFAT基序和脂质转移结构域。这种结构表明了束缚细胞器和在它们之间运输脂质的能力。我们发现，在氧固醇结合蛋白（OSBP），这两个活动耦合由一个四步循环。PH结构域和FFAT基序的膜束缚使固醇通过脂质转移结构域（ORD）转移，随后通过ORD反向转移PI（4）P。最后，PI（4）P被ER蛋白Sac 1顺式水解。PI（4）P水解提供的能量驱动甾醇转移，并在PI（4）P变得受限时允许负反馈。其他脂质转移蛋白也是通过相同的机制被束缚的。因此，OSBP介导的PI（4）P的反向转移可能会协调ER-高尔基体界面上其他脂质物质的转移。
Several proteins at endoplasmic reticulum (ER)-Golgi membrane contact sites contain a PH domain that interacts with the Golgi phosphoinositide PI(4) P, a FFAT motif that interacts with the ER protein VAP-A, and a lipid transfer domain. This architecture suggests the ability to both tether organelles and transport lipids between them. We show that in oxysterol binding protein (OSBP) these two activities are coupled by a four-step cycle. Membrane tethering by the PH domain and the FFAT motif enables sterol transfer by the lipid transfer domain (ORD), followed by back transfer of PI(4) P by the ORD. Finally, PI(4) P is hydrolyzed in cis by the ER protein Sac1. The energy provided by PI(4) P hydrolysis drives sterol transfer and allows negative feedback when PI(4) P becomes limiting. Other lipid transfer proteins are tethered by the same mechanism. Thus, OSBP-mediated back transfer of PI(4) P might coordinate the transfer of other lipid species at the ER-Golgi interface.