Ohkubo Y Zenmei, Tajkhorshid Emad
Department of Biochemistry, Beckman Institute and Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
Structure. 2008 Jan;16(1):72-81. doi: 10.1016/j.str.2007.10.021.
The GLA domain, a common membrane-anchoring domain of several serine protease coagulation factors, is a key element in membrane association and activation of these factors in a highly Ca2+-dependent manner. However, the critical role of Ca2+ ions in binding is only poorly understood. Here, we present the atomic model of a membrane-bound GLA domain by using MD simulations of the GLA domain of human factor VIIa and an anionic lipid bilayer. The binding is furnished through a complete insertion of the omega-loop into the membrane and through direct interactions of structurally bound Ca2+ ions and protein side chains with negative lipids. The model suggests that Ca2+ ions play two distinct roles in the process: the four inner Ca2+ ions are primarily responsible for optimal folding of the GLA domain for membrane insertion, whereas the outer Ca2+ ions anchor the protein to the membrane through direct contacts with lipids.
GLA结构域是几种丝氨酸蛋白酶凝血因子常见的膜锚定结构域，是以高度Ca2+依赖方式进行膜结合和这些因子激活的关键元件。然而，Ca2+离子在结合中的关键作用目前了解甚少。在此，我们通过对人因子VIIa的GLA结构域和阴离子脂质双层进行分子动力学模拟，展示了膜结合GLA结构域的原子模型。这种结合是通过ω环完全插入膜内以及结构结合的Ca2+离子和蛋白质侧链与带负电脂质的直接相互作用来实现的。该模型表明，Ca2+离子在这一过程中发挥两种不同作用：四个内部Ca2+离子主要负责GLA结构域为插入膜而进行的最佳折叠，而外部Ca2+离子则通过与脂质的直接接触将蛋白质锚定在膜上。
