Multiple lipid binding sites determine the affinity of PH domains for phosphoinositide-containing membranes.
Multiple lipid binding sites determine the affinity of PH domains for phosphoinositide-containing membranes.
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多个脂质结合位点决定 PH 结构域对含磷酸肌醇膜的亲和力。
DOI：
10.1126/sciadv.aay5736
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发表时间：
2020
期刊：
影响因子：
13.6
通讯作者：
Sansom,MarkSP
中科院分区：
文献类型：
--
作者：
Yamamoto,Eiji;Domański,Jan;Naughton,FionaB;Best,RobertB;Kalli,AntreasC;Stansfeld,PhillipJ;Sansom,MarkSP
外周蛋白与脂质双分子层的关联调节膜信号和动力学。Pleckstrin同源结构域（PH）在细胞膜上与磷酸磷脂酰肌醇（PIP）分子结合。局部PIP富集对PH结构域与膜相互作用的影响尚不清楚。分子动力学模拟可以估计GRP1 PH结构域与含pip3膜的结合能。PH结构域与两个以上pip3分子相互作用的自由能与实验值相当，表明PH结构域结合涉及到膜内PIP分子的局部聚类。我们描述了一种PH结合的机制，通过一个相遇状态到两个结合状态，这两个结合状态在蛋白质相对于膜的方向上是不同的，这些方向取决于局部的PIP浓度。这些结果表明，PIP分子的纳米级聚簇可以以浓度依赖的方式控制PH结构域相互作用的强度和方向。
Association of peripheral proteins with lipid bilayers regulates membrane signaling and dynamics. Pleckstrin homology (PH) domains bind to phosphatidylinositol phosphate (PIP) molecules in membranes. The effects of local PIP enrichment on the interaction of PH domains with membranes is unclear. Molecular dynamics simulations allow estimation of the binding energy of GRP1 PH domain to PIP3-containing membranes. The free energy of interaction of the PH domain with more than two PIP3molecules is comparable to experimental values, suggesting that PH domain binding involves local clustering of PIP molecules within membranes. We describe a mechanism of PH binding proceeding via an encounter state to two bound states which differ in the orientation of the protein relative to the membrane, these orientations depending on the local PIP concentration. These results suggest that nanoscale clustering of PIP molecules can control the strength and orientation of PH domain interaction in a concentration-dependent manner.