Supramodular nature of GRIP1 revealed by the structure of its PDZ12 tandem in complex with the carboxyl tail of Fras1
Supramodular nature of GRIP1 revealed by the structure of its PDZ12 tandem in complex with the carboxyl tail of Fras1
复制标题
GRIP1 的超模块性质通过其 PDZ12 串联结构与 Fras1 羧基尾的复合物揭示
DOI：
10.1016/j.jmb.2007.11.088
复制
发表时间：
2008-02-01
影响因子：
5.6
通讯作者：
Zhang, Mingjie
中科院分区：
文献类型：
--
作者：
Long, Jiafu;Wei, Zhiyi;Zhang, Mingjie
支架蛋白GRIP 1（谷氨酸受体相互作用蛋白1）结合并调节大量跨膜蛋白的运输和膜组织。GRIP 1在小鼠中的突变表现出与Fras 1或Frem 2突变基本相同的表型，Fras 1或Frem 2是人类遗传性疾病Fraser综合征的动物模型。然而，GRIP 1和Fras 1/Frem 2之间相互作用的分子基础是未知的。在这里，我们表明Fras 1和GRIP 1之间的相互作用需要前两个PDZ结构域（PDZ 1和PDZ 2）串联连接，因为PDZ 1的折叠严格依赖于PDZ 2的共价连接。GRIP 1 PDZ 12与Fras 1 C-末端肽复合的晶体结构揭示了PDZ 12串联形成了一个超模块，其中只有PDZ 1的肽结合沟与Fras 1肽结合。GRIP 1 PDZ 12/Fras 1肽复合物不仅提供了GRIP 1和Fraser综合征之间联系的机制解释，而且还可以作为寻找可能导致Fraser综合征的GRIP 1潜在突变的基础。(C)2007爱思唯尔有限公司版权所有。
The scaffold protein GRIP1 (glutamate receptor interacting protein 1) binds to and regulates both the trafficking and membrane organization of a large number of transmembrane proteins. Mutation of GRIP1 in mice displays essentially the same phenotype of the mutations of Fras1 or Frem2, which are the animal models of the human genetic disorder Fraser syndrome. However, the molecular basis governing the interaction between GRIP1 and Fras1/Frem2 is unknown. Here, we show that interaction between Fras1 and GRIP1 requires the first two PDZ domains (PDZ1 and PDZ2) to be connected in tandem, as the folding of PDZ1 strictly depends on the covalent attachment of PDZ2. The crystal structure of GRIP1 PDZ12 in complex with the Fras1 C-terminal peptide reveals that the PDZ12 tandem forms a supramodule in which only the peptide-binding groove of PDZ1 is bound with the Fras1 peptide. The GRIP1 PDZ12/Fras1 peptide complex not only provides a mechanistic explanation of the link between GRIP1 and the Fraser syndrome but may also serve as a foundation for searching for potential mutations in GRIP1 that could lead to the Fraser syndrome. (C) 2007 Elsevier Ltd. All rights reserved.