Computer modeling of the membrane interaction of FYVE domains
Computer modeling of the membrane interaction of FYVE domains
复制标题
DOI：
10.1016/s0022-2836(03)00325-5
复制
发表时间：
2003-05-02
影响因子：
5.6
通讯作者：
Murray, D
中科院分区：
文献类型：
--
作者：
Diraviyam, K;Stahelin, RV;Murray, D
FYVE结构域是在参与内体运输和信号转导途径的蛋白质中发现的膜靶向结构域。大多数FYVE结构域特异性结合磷脂酰肌醇3-磷酸（PI（3）P），磷脂酰肌醇3-磷酸是一种主要存在于内体膜中的脂质。虽然FYVE结构域和PI（3）P头基之间的特异性相互作用已被很好地表征，主要是通过结构研究，但现有的实验结构表明，几种不同的吸附到膜表面的模型仍有待阐明。为此，最近的实验表明，FYVE结构域结合PI（3）P在磷脂双分子层的背景下，一个保守的环上的疏水残基能够穿透膜界面的PI（3）P依赖的方式。基于计算分析，发现（1）在结构域上的碱性残基和膜中的酸性磷脂之间发生的非特异性静电相互作用促进了膜的募集，（2）能量分析可以定量地区分由实验确定的结构提出的膜缔合模式，（3）FDPB计算预测了FYVE结构域的膜结合态的能量可行模型，（4）这些模型与保守的疏水残基插入膜界面的观察一致，（5）计算结果为疏水分配提供了一个分子模型：PI（3）P的结合显著中和了疏水残基区域的正电位，通过降低膜渗透的能量屏障，起到了“静电开关”的作用。最后，通过构建高质量的人类FYVE序列同源模型，将计算结果推广到未知结构的FYVE结构域。(C)2003爱思唯尔科技有限公司版权所有。
FYVE domains are membrane targeting domains that are found in proteins involved in endosomal trafficking and signal transduction pathways. Most FYVE domains bind specifically to phosphatidylinositol 3-phosphate (PI(3)P), a lipid that resides mainly in endosomal membranes. Though the specific interactions between FYVE domains and the headgroup of PI(3)P have been well characterized, principally through structural studies, the available experimental structures suggest several different models for adsorb to the membrane surface remains to be elucidated. Towards this end, recent experiments have shown that FYVE domains bind PI(3)P in the context of phospholipid bilayers and that hydrophobic residues on a conserved loop are able to penetrate the membrane interface in a PI(3)P-dependent manner.Here, the finite difference Poisson-Boltzmann (FDPB) method has been used to calculate the energetic interactions of FYVE domains with phospholipid membranes. Based on the computational analysis, it is found that (1) recruitment to membranes is facilitated by non-specific electrostatic interactions that occur between basic residues on the domains and acidic phospholipids in the membrane, (2) the energetic analysis can quantitatively differentiate among the modes of membrane association proposed by the experimentally determined structures, (3) FDPB calculations predict energetically feasible models for the membrane-associated states of FYVE domains, (4) these models are consistent with the observation that conserved hydrophobic residues insert into the membrane interface, and (5) the calculations provide a molecular model for the hydrophobic partitioning: binding of PI(3)P significantly neutralizes positive potential in the region of the hydrophobic residues, which acts as an "electrostatic switch" by reducing the energetic barrier for membrane penetration. Finally, the computational results are extended to FYVE domains of unknown structure through the construction of high quality homology models for human FYVE sequences. (C) 2003 Elsevier Science Ltd. All rights reserved.