Role of electrostatic interactions in PDZ domain ligand recognition
Role of electrostatic interactions in PDZ domain ligand recognition
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DOI：
10.1021/bi027061p
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发表时间：
2003-03-18
期刊：
影响因子：
2.9
通讯作者：
Lim, WA
中科院分区：
文献类型：
--
作者：
Harris, BZ;Lau, FW;Lim, WA
PDZ结构域是蛋白质相互作用模块，通常识别短c端肽。由于配体的末端羧酸基团是游离的，因此提出与末端的静电相互作用在识别中起重要作用。然而，这一模型受到了最近的发现的质疑，PDZ结构域可以识别一些发生在特定二级结构背景下的内部肽基序。虽然这些基序在同一界面结合，但它们缺乏终端电荷。在这里，我们研究了静电在小鼠α - 1-syntrophin PDZ结构域中PDZ介导的识别中的作用，通过检测结合末端和内部配体的盐依赖性，以及先前提出的在静电识别中起作用的保守碱性残基突变的影响。这些研究表明，与肽端直接的静电相互作用在结合中不起重要的能量作用。对肽末端的其他化学修饰研究支持一个模型，其中空间和氢键互补在识别特异性中起主要作用。具有游离羧基末端或在特定结构环境中呈现的肽可以满足这些要求。
PDZ domains are protein-protein interaction modules that normally recognize short C-terminal peptides. The apparent requirement for a ligand with a free terminal carboxylate group has led to the proposal that electrostatic interactions with the terminus play a significant role in recognition. However, this model has been called into question by the more recent finding that PDZ domains can recognize some internal peptide motifs that occur within a specific secondary structure context. Although these motifs bind at the same interface, they lack a terminal charge. Here we have investigated the role of electrostatics in PDZ-mediated recognition in the mouse alpha1-syntrophin PDZ domain by examining the salt dependence of binding to both terminal and internal ligands and the effects of mutating a conserved basic residue previously proposed to play a role in electrostatic recognition. These studies indicate that direct electrostatic interactions with the peptide terminus do not play a significant energetic role in binding. Additional chemical modification studies of the peptide terminus support a model in which steric and hydrogen bonding complementarity play a primary role in recognition specificity. Peptides with a free carboxy terminus, or presented within a specific structural context, can satisfy these requirements.