Ligand concentration regulates the pathways of coupled protein folding and binding.
Ligand concentration regulates the pathways of coupled protein folding and binding.
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DOI：
10.1021/ja4086726
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发表时间：
2014-01-22
影响因子：
15
通讯作者：
Oas TG
中科院分区：
文献类型：
--
作者：
Daniels KG;Tonthat NK;McClure DR;Chang YC;Liu X;Schumacher MA;Fierke CA;Schmidler SC;Oas TG
偶联的配体结合和构象变化在生物调节中发挥着核心作用。配体通常通过调节构象动力学来调节蛋白质功能，但结合和构象变化发生的顺序经常引起激烈争论。在这里，我们表明这场争论所依据的“构象选择与诱导拟合”是错误的二分法，因为该机制取决于配体浓度。使用焦磷酸盐 (PPi) 与枯草芽孢杆菌 RNase P 蛋白的结合作为模型，我们表明耦合反应最好理解为具有不同结合顺序和构象变化的竞争途径之间的通量变化。每个途径的分配程度在很大程度上取决于 PPi 浓度，配体结合通过增加折叠速率和降低解折叠速率将构象整体重新分配到折叠状态。这些结果表明配体结合引起蛋白质构象动力学的显着且多样的变化，并且结合和构象变化的顺序是配体浓度依赖性的。
Coupled ligand binding and conformational change plays a central role in biological regulation. Ligands often regulate protein function by modulating conformational dynamics, yet the order in which binding and conformational change occurs are often hotly debated. Here we show that the “conformational selection versus induced fit” on which this debate is based is a false dichotomy because the mechanism depends on ligand concentration. Using the binding of pyrophosphate (PPi) to B. subtilis RNase P protein as a model, we show that coupled reactions are best understood as a change in flux between competing pathways with distinct orders of binding and conformational change. The degree of partitioning through each pathway depends strongly on PPi concentration, with ligand binding redistributing the conformational ensemble toward the folded state by both increasing folding rates and decreasing unfolding rates. These results indicate that ligand binding induces marked and varied changes in protein conformational dynamics, and that the order of binding and conformational change is ligand concentration dependent.
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