Distinct Structural and Adhesive Roles of Ca²⁺ in Membrane Binding of Blood Coagulation Factors

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 ω-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.