Long-range dynamic correlations regulate the catalytic activity of the bacterial tyrosine kinase Wzc
Long-range dynamic correlations regulate the catalytic activity of the bacterial tyrosine kinase Wzc
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DOI：
10.1126/sciadv.abd3718
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发表时间：
2020-12-01
期刊：
影响因子：
13.6
通讯作者：
Ghose, Ranajeet
中科院分区：
文献类型：
--
作者：
Hajredini, Fatlum;Piserchio, Andrea;Ghose, Ranajeet
副激酶是一类高度保守的蛋白酪氨酸激酶家族，不含真核同源基因的细菌所特有。副激酶通过一个具有稀疏机制细节的过程在C-末端酪氨酸簇上通过寡聚启动的转磷酸化来调节。利用原型BYK的催化结构域(CD)、增强采样分子动力学模拟、等温滴定量热法和核磁共振测量，我们提出了其激活和核苷酸交换的机制。我们发现，单体WZC CD优先填充具有低聚界面扭曲特征的状态，以及允许与ADP而不是与ATP.Mg2+发生高亲和力相互作用的催化元素构象。我们认为，低聚物的形成稳定了单体间的界面，并导致了催化元件构象适合最佳结合ATP.Mg2+，促进了与结合ADP的交换。这一系列的事件，齐聚，即底物结合，在与ATP.Mg2+结合之前，通过防止ATP水解的无效循环，促进了最佳的自动磷酸化。
BY-kinases represent a highly conserved family of protein tyrosine kinases unique to bacteria without eukaryotic orthologs. BY-kinases are regulated by oligomerization-enabled transphosphorylation on a C-terminal tyrosine cluster through a process with sparse mechanistic detail. Using the catalytic domain (CD) of the archetypal BY-kinase, Escherichia coli Wzc, and enhanced-sampling molecular dynamics simulations, isothermal titration calorimetry and nuclear magnetic resonance measurements, we propose a mechanism for its activation and nucleotide exchange. We find that the monomeric Wzc CD preferentially populates states characterized by distortions at its oligomerization interfaces and by catalytic element conformations that allow high-affinity interactions with ADP but not with ATP.Mg2+. We propose that oligomer formation stabilizes the intermonomer interfaces and results in catalytic element conformations suitable for optimally engaging ATP.Mg2+, facilitating exchange with bound ADP. This sequence of events, oligomerization, i.e., substrate binding, before engaging ATP.Mg2+, facilitates optimal autophosphorylation by preventing a futile cycle of ATP hydrolysis.