人源Pin1中结构域间相互作用对肽基脯氨酰异构酶活性的负调控
Negative Regulation of Peptidyl-Prolyl Isomerase Activity by Interdomain Contact in Human Pin1.
作者信息
Wang Xingsheng, Mahoney Brendan J, Zhang Meiling, Zintsmaster John S, Peng Jeffrey W
机构信息
Department of Chemistry and Biochemistry, University of Notre Dame, 251 Nieuwland Science Hall, Notre Dame, IN 46556, USA.
Department of Chemistry and Biochemistry, University of Notre Dame, 251 Nieuwland Science Hall, Notre Dame, IN 46556, USA.
出版信息
Structure. 2015 Dec 1;23(12):2224-2233. doi: 10.1016/j.str.2015.08.019. Epub 2015 Oct 22.
Pin1 is a modular peptidyl-prolyl isomerase specific for phosphorylated Ser/Thr-Pro (pS/T-P) motifs, typically within intrinsically disordered regions of signaling proteins. Pin1 consists of two flexibly linked domains: an N-terminal WW domain for substrate binding and a larger C-terminal peptidyl-prolyl isomerase (PPIase) domain. Previous studies showed that binding of phosphopeptide substrates to Pin1 could alter Pin1 interdomain contact, strengthening or weakening it depending on the substrate sequence. Thus, substrate-induced changes in interdomain contact may act as a trigger within the Pin1 mechanism. Here, we investigate this possibility via nuclear magnetic resonance studies of several Pin1 mutants. Our findings provide new mechanistic insights for those substrates that reduce interdomain contact. Specifically, the reduced interdomain contact can allosterically enhance PPIase activity relative to that when the contact is sustained. These findings suggest Pin1 interdomain contact can negatively regulate its activity.
Pin1是一种模块化的肽基脯氨酰异构酶，对磷酸化的丝氨酸/苏氨酸-脯氨酸（pS/T-P）基序具有特异性，通常存在于信号蛋白的内在无序区域内。Pin1由两个柔性连接的结构域组成：用于底物结合的N端WW结构域和较大的C端肽基脯氨酰异构酶（PPIase）结构域。先前的研究表明，磷酸肽底物与Pin1的结合可改变Pin1结构域间的接触，根据底物序列增强或减弱这种接触。因此，底物诱导的结构域间接触变化可能是Pin1机制中的一个触发因素。在这里，我们通过对几种Pin1突变体的核磁共振研究来探究这种可能性。我们的研究结果为那些减少结构域间接触的底物提供了新的机制见解。具体而言，相对于结构域间接触持续时，减少的结构域间接触可通过变构增强PPIase活性。这些发现表明Pin1结构域间接触可对其活性产生负调控作用。
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