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Interdomain Interactions Support Interdomain Communicationin Human Pin1

机译:域间交互支持域间通信在人类Pin1中

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摘要

Pin1 is an essential mitotic regulator consisting of a peptidyl–prolyl isomerase (PPIase) domain flexibly tethered to a smaller Trp–Trp (WW) binding domain. Communication between these domains is important for Pin1 in vivo activity; however, the atomic basis for this communication has remained elusive. Our previous nuclear magnetic resonance (NMR) studies of Pin1 functional dynamics suggested that weak interdomain contacts within Pin1 enable allosteric communication between the domain interface and the distal active site of the PPIase domain.1,2 A necessary condition for this hypothesis is that the intrinsic properties of the PPIase domain should be sensitive to interdomain contact. Here, we test this sensitivity by generating a Pin1 mutant, I28A, which weakens the wild-type interdomain contact while maintaining the overall folds of the two domains. Using NMR, we show that I28A leads to altered substrate binding affinity and isomerase activity. Moreover, I28A causes long-range perturbations to conformational flexibility in both domains, for both the apo and substrate-complexed states of the protein. These results show that the distribution of conformationssampled by the PPIase domain is sensitive to interdomain contact andstrengthen the hypothesis that such contact supports interdomain allostericcommunication in Pin1. Other modular systems may exploit interdomaininteractions in a similar manner.
机译:Pin1是必不可少的有丝分裂调节剂,由肽基-脯氨酰异构酶(PPIase)域灵活地束缚在较小的Trp-Trp(WW)结合域上。这些域之间的通讯对于Pin1体内活性很重要;但是,这种交流的原子基础仍然难以捉摸。我们先前对Pin1功能动力学的核磁共振(NMR)研究表明,Pin1内部的弱域间接触使域接口与PPIase域的远端活性位点之间能够进行变构通讯。1,2此假设的必要条件是固有的PPIase域的属性应对域间联系敏感。在这里,我们通过产生一个Pin1突变体I28A来测试这种敏感性,该突变体会减弱野生型域间接触,同时保持两个域的整体折叠。使用NMR,我们显示I28A导致改变的底物结合亲和力和异构酶活性。此外,对于蛋白质的载脂蛋白和底物复合状态,I28A都会在两个域中引起构象柔性的长期扰动。这些结果表明构象的分布由PPIase域采样的数据对域间联系和加强这种联系支持域间变构的假设Pin1中的通讯。其他模块化系统可能会利用域间互动方式相似。

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