Zhou X Z, Lu P J, Wulf G, Lu K P
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Cell Mol Life Sci. 1999 Nov 30;56(9-10):788-806. doi: 10.1007/s000180050026.
Protein phosphorylation on serine or threonine residues preceding proline (Ser/Thr-Pro) plays an essential role for regulating various cellular processes, including cell cycle progression. Although phosphorylation has been proposed to regulate the function of a protein by inducing conformational changes, much less is known about what phosphate additions actually do and how the functions of phosphoproteins are coordinated. Proline is important for determining protein structure because it exists in cis or trans conformation and can put kinks into a polypeptide chain. We have shown that phosphorylation on Ser/Thr-Pro motifs reduces the cis/trans isomerization rate of Ser/Thr-Pro bonds. At the same time, proteins containing phosphorylated Ser/Thr-Pro motifs are substrates for the prolyl isomerase Pin1. The WW domain of Pin1 acts as a phosphoserine/threonine-binding module binding a defined subset of mitosis-specific phosphoproteins, such as Cdc25 and tau. These interactions target the enzymatic activity of Pin1 close to its substrates. In contrast to other prolyl isomerases (peptidyl-prolyl isomerases, PPlases), Pin1 has an extremely high degree of substrate specificity, specifically isomerizing phosphorylated Ser/Thr-Pro bonds. Therefore, Pin1 binds and regulates the function of a defined subset of phosphoproteins. Furthermore, inhibiting Pin1 function is lethal for dividing cells. Interestingly, Pin1, which can restore the biological function of phosphorylated tau, is sequestered in the neurofibrillary tangles in Alzheimer's brains. Thus, we have proposed a novel signaling regulatory mechanism, where protein phosphorylation creates binding sites for Pin1, which can then latch on to and isomerize the phosphorylated Ser/Thr-Pro peptide bond. In turn, this may change the shape of the protein, regulating its activity, dephosphorylation, degradation or location in the cell. This new post-phosphorylation regulatory mechanism appears to play an important role in normal cell function, such as mitotic progression, and in the pathogenesis of some human pathologies, such as Alzheimer's disease.
脯氨酸之前的丝氨酸或苏氨酸残基上的蛋白质磷酸化（Ser/Thr-Pro）在调节包括细胞周期进程在内的各种细胞过程中起着至关重要的作用。尽管有人提出磷酸化通过诱导构象变化来调节蛋白质的功能，但对于磷酸化实际上会产生什么作用以及磷蛋白的功能是如何协调的，人们了解得还很少。脯氨酸对于确定蛋白质结构很重要，因为它以顺式或反式构象存在，并且会使多肽链产生扭结。我们已经表明，Ser/Thr-Pro基序上的磷酸化降低了Ser/Thr-Pro键的顺反异构化速率。与此同时，含有磷酸化Ser/Thr-Pro基序的蛋白质是脯氨酰异构酶Pin1的底物。Pin1的WW结构域作为一个磷酸丝氨酸/苏氨酸结合模块，结合特定的有丝分裂特异性磷蛋白子集，如Cdc25和tau。这些相互作用将Pin1的酶活性靶向其底物附近。与其他脯氨酰异构酶（肽基脯氨酰异构酶，PPlases）不同，Pin1具有极高的底物特异性，专门异构化磷酸化的Ser/Thr-Pro键。因此，Pin1结合并调节特定的磷蛋白子集的功能。此外，抑制Pin1功能对分裂细胞是致命的。有趣的是，能够恢复磷酸化tau生物学功能的Pin1被隔离在阿尔茨海默病大脑的神经原纤维缠结中。因此，我们提出了一种新的信号调节机制，其中蛋白质磷酸化产生Pin1的结合位点，然后Pin1可以附着并异构化磷酸化的Ser/Thr-Pro肽键。反过来，这可能会改变蛋白质的形状，调节其活性、去磷酸化、降解或在细胞中的定位。这种新的磷酸化后调节机制似乎在正常细胞功能（如有丝分裂进程）以及某些人类疾病（如阿尔茨海默病）的发病机制中起着重要作用。
