Long Jiafu, Wei Zhiyi, Feng Wei, Yu Cong, Zhao Yan-xiang, Zhang Mingjie
Department of Biochemistry, Molecular Neuroscience Center, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong.
J Mol Biol. 2008 Feb 1;375(5):1457-68. doi: 10.1016/j.jmb.2007.11.088. Epub 2007 Dec 4.
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.
支架蛋白GRIP1（谷氨酸受体相互作用蛋白1）与大量跨膜蛋白结合，并调节其运输和膜组织。小鼠中GRIP1的突变表现出与Fras1或Frem2突变基本相同的表型，而Fras1或Frem2是人类遗传性疾病弗雷泽综合征的动物模型。然而，GRIP1与Fras1/Frem2之间相互作用的分子基础尚不清楚。在这里，我们表明Fras1与GRIP1之间的相互作用需要前两个PDZ结构域（PDZ1和PDZ2）串联连接，因为PDZ1的折叠严格依赖于PDZ2的共价连接。GRIP1 PDZ12与Fras1 C末端肽复合物的晶体结构表明，PDZ12串联形成一个超模块，其中只有PDZ1的肽结合凹槽与Fras1肽结合。GRIP1 PDZ12/Fras1肽复合物不仅为GRIP1与弗雷泽综合征之间的联系提供了机制解释，也可能为寻找GRIP1中可能导致弗雷泽综合征的潜在突变奠定基础。
