Cation-π interactions as lipid-specific anchors for phosphatidylinositol-specific phospholipase C.
Cation-π interactions as lipid-specific anchors for phosphatidylinositol-specific phospholipase C.
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DOI：
10.1021/ja312656v
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发表时间：
2013-04-17
影响因子：
15
通讯作者：
Reuter N
中科院分区：
文献类型：
--
作者：
Grauffel C;Yang B;He T;Roberts MF;Gershenson A;Reuter N
两亲性蛋白质，例如来自苏云金芽孢杆菌的毒力因子磷脂酰肌醇特异性磷脂酶C（PI-PLC），通常依赖于靶膜的脂质特异性识别。然而，两性离子脂质，如磷脂酰胆碱，这是丰富的真核细胞的外叶的识别机制，没有很好地理解。在脂质双层表面的PI-PLC的500纳秒长的分子动力学模拟揭示了在界面结合位点处的酪氨酸与具有阳离子-π相互作用的结构特征的脂质胆碱基团之间的显著高数量的相互作用。PI-PLC酪氨酸变体的膜亲和力主要跟踪模拟结果，分为两类：（i）亲和力损失较小的那些，Kd（突变体）/Kd（野生型）≤5，和（ii）表观Kd比野生型高50-200倍的那些。从表观Kd值估算这些Tyr/PC相互作用的ΔΔG表明，与I类相关的自由能约为1 kcal/mol，与Wimley-White疏水性量表预测的值相当。相比之下，II类酪氨酸的去除具有更高的能量成本：对于纯PC囊泡约2.5千卡/摩尔。在整个MD模拟中，这些较高的能量与阳离子-π加合物的占据很好地相关。总之，这些结果强烈表明PI-PLC通过阳离子-π与酪氨酸残基的相互作用与PC头基相互作用，并表明界面处的阳离子-π相互作用可能是两性蛋白和膜蛋白特异性脂质识别的机制。
Amphitropic proteins, such as the virulence factor phosphatidylinositol-specific phospholipase C (PI-PLC) from Bacillus thuringiensis, often depend on lipid-specific recognition of target membranes. However, the recognition mechanisms for zwitterionic lipids such as phosphatidylcholine, which is enriched in the outer leaflet of eukaryotic cells, are not well understood. A 500 nanosecond long molecular dynamics simulation of PI-PLC at the surface of a lipid bilayer revealed a strikingly high number of interactions between tyrosines at the interfacial binding site and lipid choline groups with structures characteristic of cation-π interactions. Membrane affinities of PI-PLC tyrosine variants mostly tracked the simulation results, falling into two classes: (i) those with minor losses in affinity, Kd(mutant)/Kd(wildtype)≤5, and (ii) those where the apparent Kd was 50-200 times higher than wildtype. Estimating ΔΔG for these Tyr/PC interactions from the apparent Kd values reveals that the free energy associated with class I is ~1 kcal/mol, comparable to the value predicted by the Wimley-White hydrophobicity scale. In contrast, removal of class II tyrosines has a higher energy cost: ~2.5 kcal/mol towards pure PC vesicles. These higher energies correlate well with the occupancy of the cation-π adducts throughout the MD simulation. Together, these results strongly indicate that PI-PLC interacts with PC headgroups via cation-π interactions with tyrosine residues, and suggest that cation-π interactions at the interface may be a mechanism for specific lipid recognition by amphitropic and membrane proteins.
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影响因子：
3.3
作者：
Klauda, Jeffery B.;Venable, Richard M.;Freites, J. Alfredo;O'Connor, Joseph W.;Tobias, Douglas J.;Mondragon-Ramirez, Carlos;Vorobyov, Igor;MacKerell, Alexander D., Jr.;Pastor, Richard W.
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影响因子：
15
作者：
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通讯作者：
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作者：
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通讯作者：
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影响因子：
4.4
作者：
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通讯作者：
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影响因子：
4.4
作者：
Izaguirre, JA;Reich, S;Skeel, RD
通讯作者：
Skeel, RD