An allosteric intramolecular PDZ-PDZ interaction modulates PTP-BL PDZ2 binding specificity.
An allosteric intramolecular PDZ-PDZ interaction modulates PTP-BL PDZ2 binding specificity.
复制标题
变构分子内 PDZ-PDZ 相互作用调节 PTP-BL PDZ2 结合特异性。
作者：
Lieke C. J. van den Berk;Elena Landi;T. Walma;G. W. Vuister;L. Dente;W. Hendriks
PDZ(突触相关蛋白PSD-95/SAP90、间隔连接蛋白Discs-Large和紧密连接蛋白ZO-1)结构域是丰富的小球状蛋白相互作用结构域，主要识别其靶蛋白的羧基末端。对PDZ结构域结合特异性的详细了解是理解他们建立的相互作用网络的先决条件。我们通过筛选随机C端肽Lambda噬菌体展示文库，确定了蛋白酪氨酸磷酸酶PTP-BL中5个PDZ结构域的结合偏好。有趣的是，PDZ2与III型配体相互作用的潜力被发现受到PDZ1的存在的调节。结构研究表明，PDZ1与PDZ2上与多肽结合槽相反的表面存在直接和特异的相互作用。导致PDZ2肽结合槽结构变化的长程变构效应因此解释了PDZ2结合偏好的改变。我们的实验结果证实了PDZ结构域的分子嵌入是其配体结合特异性的重要决定因素。
PDZ (acronym of the synapse-associated protein PSD-95/SAP90, the septate junction protein Discs-large, and the tight junction protein ZO-1) domains are abundant small globular protein interaction domains that mainly recognize the carboxyl termini of their target proteins. Detailed knowledge on PDZ domain binding specificity is a prerequisite for understanding the interaction networks they establish. We determined the binding preference of the five PDZ domains in the protein tyrosine phosphatase PTP-BL by screening a random C-terminal peptide lambda phage display library. Interestingly, the potential of PDZ2 to interact with class III-type ligands was found to be modulated by the presence of PDZ1. Structural studies revealed a direct and specific interaction of PDZ1 with a surface on PDZ2 that is opposite the peptide binding groove. Long-range allosteric effects that cause structural changes in the PDZ2 peptide binding groove thus explain the altered PDZ2 binding preference. Our results experimentally corroborate that the molecular embedding of PDZ domains is an important determinant of their ligand binding specificity.