Uncorrelated Effect of Interdomain Contact on Pin1 Isomerase Activity Reveals Positive Catalytic Cooperativity
Uncorrelated Effect of Interdomain Contact on Pin1 Isomerase Activity Reveals Positive Catalytic Cooperativity
复制标题
域间接触对 Pin1 异构酶活性的不相关影响揭示了正催化协同作用
DOI：
10.1021/acs.jpclett.9b00052
复制
发表时间：
2019
影响因子：
5.7
通讯作者：
Yang Yunhuang
中科院分区：
文献类型：
--
作者：
Zhu Wenkai;Li Ying;Liu Maili;Zhu Jiang;Yang Yunhuang
Pin1是一种与神经变性和肿瘤发生相关的双结构域肽基脯氨酰异构酶（PPIase）。两个结构域，WW和PPIase结构域，通过柔性接头连接，使得Pin1采用从紧凑到扩展的各种构象，其中Pin1表现出不同程度的结构域间接触。以前的研究表明，削弱域间接触增加Pin1的异构酶活性。在这里，我们提出了一个NMR化学位移相关分析为基础的方法，将是一般的两个结构域的蛋白质，以衡量两个国家的人口Pin1，我们报告了一个接头修饰的突变体Pin1增强域间接触和异构酶活性增加，后者表明异构酶活性的域间接触的不相关的影响。因此，尽管WW结构域中不同底物的结合对结构域间接触产生相反的影响，但在这两种情况下，它可能促进异构化，这意味着WW结构域中底物结合与PPIase结构域中异构化之间的协同性。
Pin1 is a two-domain peptidyl–prolyl isomerase (PPIase) associated with neurodegeneration and tumorigenesis. The two domains, a WW and a PPIase domain, are connected by a flexible linker, making Pin1 adopt various conformations ranging from compact to extended, wherein Pin1 exhibits different extents of interdomain contact. Previous studies have shown that weakening interdomain contact increases the isomerase activity of Pin1. Here, we propose an NMR chemical shift correlation-analysis-based method that will be general for two-domain proteins to gauge two-state populations of Pin1, and we report a linker-modified mutant of Pin1 with enhanced interdomain contact and increased isomerase activity, with the latter suggesting an uncorrelated effect of interdomain contact on isomerase activity. Thus, although bindings of different substrates in the WW domain impose opposite effects on interdomain contact, in both cases, it may promote isomerization, implying cooperativity between substrate binding in the WW domain and isomerization in the PPIase domain.