Huang Mingdong, Rigby Alan C, Morelli Xavier, Grant Marianne A, Huang Guiqing, Furie Bruce, Seaton Barbara, Furie Barbara C
Center for Hemostasis and Thrombosis Research, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA.
Nat Struct Biol. 2003 Sep;10(9):751-6. doi: 10.1038/nsb971. Epub 2003 Aug 17.
In a calcium-dependent interaction critical for blood coagulation, vitamin K-dependent blood coagulation proteins bind cell membranes containing phosphatidylserine via gamma-carboxyglutamic acid-rich (Gla) domains. Gla domain-mediated protein-membrane interaction is required for generation of thrombin, the terminal enzyme in the coagulation cascade, on a physiologic time scale. We determined by X-ray crystallography and NMR spectroscopy the lysophosphatidylserine-binding site in the bovine prothrombin Gla domain. The serine head group binds Gla domain-bound calcium ions and Gla residues 17 and 21, fixed elements of the Gla domain fold, predicting the structural basis for phosphatidylserine specificity among Gla domains. Gla domains provide a unique mechanism for protein-phospholipid membrane interaction. Increasingly Gla domains are being identified in proteins unrelated to blood coagulation. Thus, this membrane-binding mechanism may be important in other physiologic processes.
在对血液凝固至关重要的钙依赖性相互作用中，维生素K依赖性血液凝固蛋白通过富含γ-羧基谷氨酸（Gla）的结构域与含有磷脂酰丝氨酸的细胞膜结合。在生理时间尺度上，凝血级联反应中的终端酶凝血酶的生成需要Gla结构域介导的蛋白质-膜相互作用。我们通过X射线晶体学和核磁共振光谱确定了牛凝血酶原Gla结构域中的溶血磷脂酰丝氨酸结合位点。丝氨酸头部基团结合Gla结构域结合的钙离子以及Gla结构域折叠的固定元件Gla残基17和21，这预测了Gla结构域之间磷脂酰丝氨酸特异性的结构基础。Gla结构域为蛋白质-磷脂膜相互作用提供了一种独特的机制。越来越多与血液凝固无关的蛋白质中发现了Gla结构域。因此，这种膜结合机制可能在其他生理过程中很重要。
