Landrieu Isabelle, Smet C, Wieruszeski J-M, Sambo A-V, Wintjens R, Buée L, Lippens G
CNRS UMR 8576, Université des Sciences et Technologies de Lille, 59655 Villeneuve d'Ascq, France.
Curr Protein Pept Sci. 2006 Jun;7(3):179-94. doi: 10.2174/138920306777452303.
PIN1 participates in the regulation of a number of signalling pathways in the cell involving protein phosphorylation/dephosphorylation. Its role seems to be an essential control level in addition to the protein phosphorylation by proline-directed kinases. Its cellular function includes regulation of the cell cycle by interaction with phosphorylated mitotic proteins such as Cdc25 and transcription factors such as p53. PIN1 was shown to be involved in the malignant transformation of cells in breast cancer, by up regulation of cyclinD1 and is thought to be involved in the development of the AD by regulating the function of phosphorylated Tau. We propose here to discuss the molecular function of PIN1 at the atomic level based on data from the recent literature and our own results obtained by the technique of Nuclear Magnetic Resonance. PIN1 specifically interacts with pThr/pSer-Pro motifs and is constituted by two domains: a WW N-terminal domain that binds pThr/pSer-Pro epitopes and a prolyl cis/trans isomerase C-terminal catalytic domain. An exception to this organisation is found in the plant PIN1 homologous enzymes, like PIN1At from Arabidopsis thaliana, that are constituted of the sole catalytic domain. The molecular function of PIN1, binding to and isomerization of pThr/pSer-Pro bonds, are thought to lead to several functional consequences. In a first mode of action, exemplified by its competition with the CKS protein, the interaction with PIN1 prevents interaction with other regulatory proteins, like ubiquitin-ligases that lead to degradation pathways. In a second mode of action, the idea is largely accepted that the local isomerization modifies the global conformation of the protein substrate and hence its intrinsic activity, although this has never been directly demonstrated. Finally, isomerization catalysis is thought to regulate the (de)phosphorylation of specific pThr/pSer-Pro motifs, exemplified by the stimulation of the dephosphorylation of pThr231 of Tau by the PP2A phosphatase.
PIN1参与细胞内多种涉及蛋白质磷酸化/去磷酸化的信号通路调控。除脯氨酸定向激酶介导的蛋白质磷酸化外，其作用似乎是一个重要的调控水平。其细胞功能包括通过与磷酸化的有丝分裂蛋白（如Cdc25）和转录因子（如p53）相互作用来调节细胞周期。PIN1已被证明通过上调细胞周期蛋白D1参与乳腺癌细胞的恶性转化，并被认为通过调节磷酸化Tau的功能参与阿尔茨海默病（AD）的发展。在此，我们基于近期文献数据以及我们自己通过核磁共振技术获得的结果，讨论PIN1在原子水平上的分子功能。PIN1特异性地与pThr/pSer-Pro基序相互作用，由两个结构域组成：一个结合pThr/pSer-Pro表位的WW N端结构域和一个脯氨酰顺/反异构酶C端催化结构域。在植物PIN1同源酶中发现了这种结构的一个例外，如拟南芥的PIN1At，它仅由催化结构域组成。PIN1与pThr/pSer-Pro键的结合及异构化的分子功能被认为会导致多种功能后果。在第一种作用模式中，以其与CKS蛋白的竞争为例，与PIN1的相互作用可防止与其他调节蛋白（如导致降解途径的泛素连接酶）相互作用。在第二种作用模式中，虽然尚未直接证实，但人们普遍认为局部异构化会改变蛋白质底物的整体构象，从而改变其内在活性。最后，异构化催化被认为可调节特定pThr/pSer-Pro基序的（去）磷酸化，例如PP2A磷酸酶对Tau的pThr231去磷酸化的刺激作用。
