Biological Activities of Protein Folding Enzyme

蛋白质的磷酸化是细胞中一种重要的生物信号，对信号转导、细胞周期进程和细胞凋亡等过程至关重要。众所周知，磷酸基团的加入可以使蛋白质承担与其未磷酸化形式不同的生物学作用。然而，目前尚不清楚的是所观察到的磷酸化导致的功能变化的结构基础。肽基脯氨酰顺-反式异构酶(PPIase)催化脯氨酸肽键的顺反异构化，是细胞蛋白质组装、折叠和运输所必需的。Pin1是Popilion家族的一种PPIase，Chat对细胞信号可能特别重要，因为除了PPIase结构域之外，它的N端还有一个WW结构域，可以识别几种蛋白质中的磷酸丝氨酸(PSer)或磷酸苏氨酸(PThr)-Pro基序并与其相互作用。具体来说，Pin1与pSer/pThr-Pro序列结合并异构化pSer/pThr-Pro键，以磷酸化依赖的方式改变蛋白质构象和/或促进蛋白质去磷酸化。这有力地支持了Pin1作为磷酸化蛋白质功能变化的一个组成部分的作用。在小鼠中，Pin1基因的敲除导致了可存活的后代，尽管有可检测到的表型，如视网膜萎缩、怀孕期间乳腺上皮扩张受损、不育和年龄依赖性神经退化。对Pin1-KO小鼠制备的细胞的分析表明，Pin1正向调节p53的水平和活性，并控制c-myc的降解。我们还筛选了化学文库，并鉴定了一系列的抑制剂。它们被用来证明Pin1对细胞周期进程是重要的。

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.