Phosphatidylinositol phosphates modulate interactions between the StarD4 sterol trafficking protein and lipid membranes.
Phosphatidylinositol phosphates modulate interactions between the StarD4 sterol trafficking protein and lipid membranes.
复制标题
磷脂酰肌醇磷酸调节StarD4固醇运输蛋白和脂质膜之间的相互作用。
DOI：
10.1016/j.jbc.2022.102058
复制
发表时间：
2022-07
影响因子：
4.8
通讯作者：
Max, Frederick R.
中科院分区：
文献类型：
--
作者：
Zhang, Xiaoxue;Xie, Hengyi;Iaea, David;Khelashvili, George;Weinstein, Harel;Max, Frederick R.
有大量证据表明细胞中存在广泛的非囊泡甾醇转运。例如，含有 StarT 结构域的类固醇生成急性调节相关蛋白 (StarD) 的脂质转移已被证明涉及多种非囊泡运输途径。在含可溶性 StarT 结构域的蛋白中，StarD4 在大多数组织中表达，并已被证明是一种有效的甾醇转移蛋白。然而，尚不清楚供体膜或受体膜的脂质成分是否在调节 StarD4 介导的转运中发挥作用。在这里，我们使用基于荧光的测定来证明磷酸磷脂酰肌醇 (PIP) 选择性机制，通过该机制 StarD4 可以优先从含有某些 PIP（特别是 PI(4,5)P2 和较小程度的 PI(3,5)P2）的脂质体膜中提取甾醇。单磷酸化 PIP 和其他阴离子脂质对甾醇转运的影响较小。当受体膜中存在相同的 PIP 时，这种运输增强效果较差。此外，利用分子动力学 (MD) 模拟，我们绘制了 StarD4 与含有 PIP 的膜的关键相互作用位点，并确定了对于这种相互作用和加速甾醇转运活性非常重要的残基。我们表明，StarD4 通过与 PIP 头基几何结构以及周围膜环境的特定相互作用来识别膜特异性 PIP。最后，我们还观察到 StarD4 在较长时间的孵育后会使膜变形。总而言之，这些结果表明 PIP 通过 StarD4 调节胆固醇转移活性的机制。
There is substantial evidence for extensive nonvesicular sterol transport in cells. For example, lipid transfer by the steroidogenic acute regulator-related proteins (StarD) containing a StarT domain has been shown to involve several pathways of nonvesicular trafficking. Among the soluble StarT domain–containing proteins, StarD4 is expressed in most tissues and has been shown to be an effective sterol transfer protein. However, it was unclear whether the lipid composition of donor or acceptor membranes played a role in modulating StarD4-mediated transport. Here, we used fluorescence-based assays to demonstrate a phosphatidylinositol phosphate (PIP)-selective mechanism by which StarD4 can preferentially extract sterol from liposome membranes containing certain PIPs (especially, PI(4,5)P2 and to a lesser degree PI(3,5)P2). Monophosphorylated PIPs and other anionic lipids had a smaller effect on sterol transport. This enhancement of transport was less effective when the same PIPs were present in the acceptor membranes. Furthermore, using molecular dynamics (MD) simulations, we mapped the key interaction sites of StarD4 with PIP-containing membranes and identified residues that are important for this interaction and for accelerated sterol transport activity. We show that StarD4 recognizes membrane-specific PIPs through specific interaction with the geometry of the PIP headgroup as well as the surrounding membrane environment. Finally, we also observed that StarD4 can deform membranes upon longer incubations. Taken together, these results suggest a mechanism by which PIPs modulate cholesterol transfer activity via StarD4.
登录
查看更多内容
影响因子：
3
作者：
Kremer, JR;Mastronarde, DN;McIntosh, JR
通讯作者：
McIntosh, JR
DOI：
10.1016/j.bbalip.2020.158609
发表时间：
2020-04-01
影响因子：
4.8
作者：
Iaea, David B.;Spahr, Zachary R.;Maxfield, Frederick R.
通讯作者：
Maxfield, Frederick R.
影响因子：
0.9
作者：
Dikiy I;Ramlall TF;Eliezer D
通讯作者：
Eliezer D
影响因子：
4.3
作者：
Eastman P;Swails J;Chodera JD;McGibbon RT;Zhao Y;Beauchamp KA;Wang LP;Simmonett AC;Harrigan MP;Stern CD;Wiewiora RP;Brooks BR;Pande VS
通讯作者：
Pande VS
影响因子：
3.4
作者：
Khelashvili, George;Harries, Daniel;Weinstein, Harel
通讯作者：
Weinstein, Harel