Blomberg N, Nilges M
European Molecular Biology Laboratory, Heidelberg, Germany.
Fold Des. 1997;2(6):343-55. doi: 10.1016/S1359-0278(97)00048-5.
Pleckstrin homology (PH) domains are found in many proteins involved in signal transduction or cytoskeletal organization. The general function for the domain is still unclear; phospholipid binding of some PH domains and a strong electrostatic polarization in the experimental structures suggest a role in localization on membranes. We have analyzed the electrostatic properties and the spatial amino acid distribution from homology models of the entire PH domain family.
Despite the sequence divergence, the quality of the models is sufficient for our study. Most PH domains have an electrostatic polarization similar to the experimental structures. but roughly half of the PH domains linked to a Dbl homology domain have very different electrostatic properties. We also found a striking electrostatic complementarity in some internal PH domain repeats. The analysis of the spatial distribution of amino acids identified residues in the phospholipid-binding site of the spectrin and dynamin PH domains as specific for these domains.
The mostly conserved electrostatic polarization supports a general function in binding to phospholipid membranes. But the presence of PH domains with opposite polarity suggests that ligands and functions have diverged during evolution. We also demonstrate homology modelling as a general sequence analysis tool that can yield significantly more information than conventional analysis.
普列克底物蛋白同源（PH）结构域存在于许多参与信号转导或细胞骨架组织的蛋白质中。该结构域的一般功能仍不清楚；一些PH结构域与磷脂的结合以及实验结构中的强静电极化表明其在膜定位中起作用。我们分析了整个PH结构域家族同源模型的静电性质和空间氨基酸分布。
尽管序列存在差异，但模型质量足以满足我们的研究需求。大多数PH结构域具有与实验结构相似的静电极化。但是，大约一半与Dbl同源结构域相连的PH结构域具有非常不同的静电性质。我们还在一些内部PH结构域重复序列中发现了显著的静电互补性。对氨基酸空间分布的分析确定了血影蛋白和发动蛋白PH结构域磷脂结合位点中的残基是这些结构域所特有的。
大多数保守的静电极化支持了与磷脂膜结合的一般功能。但是具有相反极性的PH结构域的存在表明，在进化过程中配体和功能已经发生了分化。我们还证明了同源建模作为一种通用的序列分析工具，能够产生比传统分析更多的信息。
