Solution structure and backbone dynamics of the AF-6 PDZ domain/Bcr peptide complex
Solution structure and backbone dynamics of the AF-6 PDZ domain/Bcr peptide complex
复制标题
AF-6 PDZ 结构域/Bcr 肽复合物的溶液结构和骨架动力学
DOI：
10.1110/ps.062440607
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发表时间：
2007-06-01
期刊：
影响因子：
8
通讯作者：
Shi, Yunyu
中科院分区：
文献类型：
--
作者：
Chen, Quan;Niu, Xiaogang;Shi, Yunyu
人AF-6是细胞膜相关蛋白和肌动蛋白细胞骨架之间的支架蛋白，在特殊的细胞连接和信号转导中起重要作用。它可以被蛋白激酶Bcr磷酸化，这使得Bcr的C末端与AF-6的PDZ结构域有效结合，从而增强AF-6与Ras的结合亲和力。AF-6、Bcr和Ras三元复合物的形成导致Ras介导的信号转导途径的下调。为了更好地理解AF-6 PDZ结构域和Bcr识别的分子基础，我们解决了AF-6 PDZ结构域与Bcr的C-末端肽复合的溶液结构，并详细探索它们之间的相互作用。与以前报道的结构相比，该复合物表现出非经典的PDZ/肽的结合模式。由于AF-6 PDZ结构域和Bcr肽相互作用中涉及不同的残基，因此相互作用模式不适合基于配体或PDZ结构域特异性提出的现有分类规则。此外，AF-6的PDZ结构域可以在AF-6被Bcr激酶磷酸化后有效地结合到Bcr的C末端。磷酸化可以诱导AF-6的构象变化，这使得PDZ结构域上的结合表面可接近Bcr以进行有效结合。该研究不仅表征了AF-6 PDZ/Bcr肽复合物的结构细节，而且为未来的药物设计和疾病治疗提供了潜在的靶点。
The human AF-6, a scaffold protein between cell membrane-associated proteins and the actin cytoskeleton, plays an important role in special cell-cell junctions and signal transduction. It can be phosphorylated by the protein kinase Bcr, which allows efficient binding of the C terminus of Bcr to the PDZ domain of AF-6 and consequently enhances the binding affinity of AF-6 to Ras. Formation of the AF-6, Bcr, and Ras ternary complex results in down-regulation of the Ras-mediated signal transduction pathway. To better understand the molecular basis for the recognition of the AF-6 PDZ domain and Bcr, we solve the solution structure of the AF-6 PDZ domain complexed with the C-terminal peptide of Bcr and explore the interactions between them in detail. Compared with previously reported structures, the complex exhibits a noncanonical binding mode of PDZ/peptide. Owing to the distinct residues involved in the AF-6 PDZ domain and Bcr peptide interaction, the interaction mode does not adapt to the existing classification rules that have been put forward, based on the ligand or the PDZ domain specificity. Furthermore, the PDZ domain of AF-6 can bind to the C terminus of Bcr efficiently after phosphorylation of AF-6 by the Bcr kinase. The phosphorylation may induce a conformational change of AF-6, which makes the binding surface on the PDZ domain accessible to Bcr for efficient binding. This study not only characterizes the structural details of the AF-6 PDZ/Bcr peptide complex, but also provides a potential target for future drug design and disease therapy.