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首页> 外文期刊>Journal of Molecular Biology >Structural and functional studies of γ-carboxyglutamic acid domains of factor VIIa and activated protein C: Role of magnesium at physiological calcium
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Structural and functional studies of γ-carboxyglutamic acid domains of factor VIIa and activated protein C: Role of magnesium at physiological calcium

机译：VIIa因子和活化蛋白C的γ-羧基谷氨酸结构域的结构和功能研究：镁在生理钙中的作用

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摘要

Crystal structures of factor (F) VIIa/soluble tissue factor (TF), obtained under high Mg2 + (50 mM Mg2 +/5 mM Ca2 +), have three of seven Ca2 + sites in the γ-carboxyglutamic acid (Gla) domain replaced by Mg2 + at positions 1, 4, and 7. We now report structures under low Mg2 + (2.5 mM Mg2 +/5 mM Ca 2 +) as well as under high Ca2 + (5 mM Mg2 +/45 mM Ca2 +). Under low Mg2 +, four Ca2 + and three Mg2 + occupy the same positions as in high-Mg2 + structures. Conversely, under low Mg2 +, reexamination of the structure of Gla domain of activated Protein C (APC) complexed with soluble endothelial Protein C receptor (sEPCR) has position 4 occupied by Ca 2 + and positions 1 and 7 by Mg2 +. Nonetheless, in direct binding experiments, Mg2 + replaced three Ca2 + sites in the unliganded Protein C or APC. Further, the high-Ca2 + condition was necessary to replace Mg4 in the FVIIa/soluble TF structure. In biological studies, Mg2 + enhanced phospholipid binding to FVIIa and APC at physiological Ca2 +. Additionally, Mg2 + potentiated phospholipid-dependent activations of FIX and FX by FVIIa/TF and inactivation of activated factor V by APC. Since APC and FVIIa bind to sEPCR involving similar interactions, we conclude that under the low-Mg2 + condition, sEPCR binding to APC-Gla (or FVIIa-Gla) replaces Mg4 by Ca4 with an attendant conformational change in the Gla domain ω-loop. Moreover, since phospholipid and sEPCR bind to FVIIa or APC via the ω-loop, we predict that phospholipid binding also induces the functional Ca4 conformation in this loop. Cumulatively, the data illustrate that Mg2 + and Ca 2 + act in concert to promote coagulation and anticoagulation.
机译：在高Mg2 +（50 mM Mg2 + / 5 mM Ca2 +）下获得的因子（F）VIIa /可溶性组织因子（TF）的晶体结构在γ-羧基谷氨酸（Gla）域中有七个Ca2 +位点中的三个在位置1、4和7处被Mg2 +取代。我们现在报告低Mg2 +（2.5 mM Mg2 + / 5 mM Ca 2 +）以及高Ca2 +（5 mM Mg2 + / 45 mM Ca2 +下的结构）。在低Mg2 +下，四个Ca2 +和三个Mg2 +占据与高Mg2 +结构相同的位置。相反，在低Mg2 +浓度下，与可溶性内皮蛋白C受体（sEPCR）复合的活化蛋白C（APC）的Gla结构域的结构重新检查，Ca 2 +占据4位，Mg2 +占据1和7位。但是，在直接结合实验中，Mg2 +取代了未配体的C蛋白或APC中的三个Ca2 +位点。此外，必须使用高Ca2 +条件来替换FVIIa /可溶性TF结构中的Mg4。在生物学研究中，Mg2 +在生理Ca2 +处增强了与FVIIa和APC的磷脂结合。另外，Mg2 +通过FVIIa / TF增强了FIX和FX的磷脂依赖性激活，并通过APC激活了活化的因子V。由于APC和FVIIa与sEPCR结合并涉及相似的相互作用，因此我们得出结论，在低Mg2 +条件下，与APC-Gla（或FVIIa-Gla）结合的sEPCR用Ca4取代Mg4，伴随着Gla结构域ω环的构象变化。此外，由于磷脂和sEPCR通过ω环与FVIIa或APC结合，我们预测磷脂结合也会在此环中诱导功能性Ca4构象。累积地，数据表明Mg2 +和Ca 2 +协同作用以促进凝结和抗凝。

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