Biological Activities of Protein Folding Enzyme

蛋白质折叠酶的生物活性

基本信息

批准号：
13460148
负责人：
UCHIDA Takafumi
金额：
$ 8.13万
依托单位：
Tohoku University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2003
项目状态：
已结题

项目摘要

The phosphorylation of proteins is a vital biological signal in cells, critical for processes such as signal transduction, cell cycle progression, and apoptosis. It is well documented that the addition of a phosphate group can cause a protein to assume a different biological role from its unphosphorylated form. However, what is not understood is the structural basis for the observed functional changes as a result of phosphorylation. Peptidyl prolyl cis-trans isomerase (PPIase) catalyzes the cis-trans isomerization of prolyl peptide bonds, and PPIase activity is required for the assembly, folding, and transport of cellular proteins. Pin1 is a PPIase from the pavilion family chat may be particularly important for cell signaling because, in addition to its PPIase domain, it has a WW domain at its N terminus that recognizes and interacts with phosphoserine (pSer) or phosphothreonine (pThr)-proline motifs in several proteins. Specifically, Pin1 binds to pSer/pThr-Pro sequences and isomerizes pSer/pThr-Pro bonds, altering the protein conformation in a phosphorylation-dependent manner and/or promoting protein dephosphorylation. This strongly supports a role for Pin1 as an integral component of the change in function of phosphorylated proteins. In mice, a knockout of the Pin1 gene resulted in viable offspring, albeit with detectable phenotypes, such as such as retinal atrophy, impaired mammary epithelial expansion during pregnancy, infertile and age-dependent neurodegeneration. The analysis of the cells prepared from Pin1-KO mice showed that Pin1 regulates the level and the activities of p53 positively and Pin1 controls c-myc degradation. We also screened chemical library and identified a series of inhibitors. They were used to show that Pin1 is important for cell cycle progression.

蛋白质的磷酸化是细胞中重要的生物学信号，对于诸如信号转导，细胞周期进程和凋亡等过程至关重要。有充分的文献证明，磷酸组的添加会导致蛋白质具有与其未磷酸化形式不同的生物学作用。但是，尚不清楚的是观察到的功能变化的结构基础，这是由于磷酸化而导致的。肽基prolyl prolyl prolyl trans异构酶（PPIASE）催化prolyl肽键的顺式传播异构化，而细胞蛋白的组装，折叠和运输需要PPIASE活性。 PIN1是凉亭家族聊天中的PPIASE，对于细胞信号传导可能尤其重要，因为除了其N末端还具有WW结构域，其n末端具有识别并与多种蛋白质中的磷酸（PSER）或磷酸硫氰酸（PTHR） - 磷酸苯胺（PTHR） - 磷酸蛋白基序相互作用。具体而言，PIN1与PSER/PTHR-PRO序列结合，并异构化PSER/PTHR-PRO键，以磷酸化依赖性的方式改变蛋白质构象和/或促进蛋白质去磷酸化。这强烈支持PIN1作为磷酸化蛋白功能变化的组成部分的作用。在小鼠中，PIN1基因的敲除导致了可行的后代，尽管具有可检测的表型，例如视网膜萎缩，妊娠期间乳腺上皮膨胀受损。对PIN1-KO小鼠制备的细胞的分析表明，PIN1调节p53的水平和活性，而PIN1控制C-Myc降解。我们还筛选了化学文库，并确定了一系列抑制剂。它们被用来表明PIN1对于细胞周期进程很重要。