Department of Chemistry, University of Illinois at Chicago, Chicago, IL 60607, USA.
Mol Cell. 2012 Apr 27;46(2):226-37. doi: 10.1016/j.molcel.2012.02.012. Epub 2012 Mar 22.
Emerging evidence indicates that membrane lipids regulate protein networking by directly interacting with protein-interaction domains (PIDs). As a pilot study to identify and functionally annodate lipid-binding PIDs on a genomic scale, we performed experimental and computational studies of PDZ domains. Characterization of 70 PDZ domains showed that ~40% had submicromolar membrane affinity. Using a computational model built from these data, we predicted the membrane-binding properties of 2,000 PDZ domains from 20 species. The accuracy of the prediction was experimentally validated for 26 PDZ domains. We also subdivided lipid-binding PDZ domains into three classes based on the interplay between membrane- and protein-binding sites. For different classes of PDZ domains, lipid binding regulates their protein interactions by different mechanisms. Functional studies of a PDZ domain protein, rhophilin 2, suggest that all classes of lipid-binding PDZ domains serve as genuine dual-specificity modules regulating protein interactions at the membrane under physiological conditions.
新出现的证据表明，膜脂通过与蛋白相互作用结构域（PID）直接相互作用来调节蛋白网络。作为在基因组范围内识别和功能注释脂结合 PID 的初步研究，我们对 PDZ 结构域进行了实验和计算研究。对 70 个 PDZ 结构域的特性分析表明，约 40%的 PDZ 结构域具有亚微米级的膜亲和力。利用从这些数据构建的计算模型，我们预测了来自 20 个物种的 2000 个 PDZ 结构域的膜结合特性。对于 26 个 PDZ 结构域，预测的准确性通过实验得到了验证。我们还根据膜结合和蛋白结合位点之间的相互作用，将脂结合 PDZ 结构域细分为三类。对于不同类别的 PDZ 结构域，脂质结合通过不同的机制调节它们的蛋白相互作用。对 PDZ 结构域蛋白 rho 蛋白 2 的功能研究表明，所有类别的脂结合 PDZ 结构域都作为真正的双特异性模块，在生理条件下在膜上调节蛋白相互作用。
