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首页> 外文期刊>Journal of thrombosis and haemostasis: JTH >Hydrogen‐deuterium exchange mass spectrometry highlights conformational changes induced by factor XI XI activation and binding of factor IX IX to factor XI XI a
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Hydrogen‐deuterium exchange mass spectrometry highlights conformational changes induced by factor XI XI activation and binding of factor IX IX to factor XI XI a

机译：氢 - 氘交换质谱突出显示因子XI XI激活和因子IX IX的结合引起的构象变化，对因子xi xi a

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Abstract Background Factor XI ( FXI ) is a zymogen in the coagulation pathway that, once activated, promotes haemostasis by activating factor IX ( FIX ). Substitution studies using apple domains of the homologous protein prekallikrein have identified that FIX binds to the apple 3 domain of FXI . However, the molecular changes upon activation of FXI or binding of FIX to FXI a have remained largely unresolved. Objectives This study aimed to gain more insight in the FXI activation mechanism by identifying the molecular differences between FXI and FXI a, and in the conformational changes in FXI a induced by binding of FIX . Methods Hydrogen‐deuterium exchange mass spectrometry was performed on FXI , FXI a, and FXI a in complex with FIX . Results Both activation and binding to FIX induced conformational changes at the interface between the catalytic domain and the apple domains of FXI (a)—more specifically at the loops connecting the apple domains. Moreover, introduction of FIX uniquely induced a reduction of deuterium uptake in the beginning of the apple 3 domain. Conclusions We propose that the conformational changes of the catalytic domain upon activation increase the accessibility to the apple 3 domain to enable FIX binding. Moreover, our HDX MS results support the location of the proposed FIX binding site at the beginning of the apple 3 domain and suggest a mediating role in FIX binding for both loops adjacent to the apple 3 domain.
机译：摘要背景系数因子Xi（FXI）是凝血途径中的酶原，即一旦被激活，通过激活因子IX（修复）促进肝脏。使用同源蛋白前蛋白前蛋白质的苹果域的替代研究已经确定了固定与FXI的苹果3结构域结合。然而，在激活FXI或固定到FXI A的结合后的分子变化仍未得到尚未解决。目的本研究旨在通过鉴定FXI和FXI A之间的分子差异，并通过修复结合诱导的FXI A的构象变化，在FXI激活机制中获得更多洞察力。方法对FXI，FXI A和FXI A进行氢 - 氘交换质谱法在复合物中进行复合物。结果激活和结合在催化结构域和FXI（a）的催化结构域和苹果领域之间的界面处的诱导构象变化 - 摩尔在连接苹果结构域的环路上。此外，在苹果3结构域的开头唯一地诱导唯一诱导氘摄取的减少。结论我们提出了催化结构域对激活后的构象变化增加了对苹果3结构域的可接近性，以使固定结合。此外，我们的HDX MS结果支持苹果3结构域的开始时所提出的修复结合位点的位置，并建议在苹果3结构域附近的两个环路的固定结合中的中介作用。

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