Structure of the Ca(2+)-free Gla domain sheds light on membrane binding of blood coagulation proteins.

Reversible membrane binding of gamma-carboxyglutamic acid (Gla)-containing coagulation factors requires Ca(2+)-binding to 10-12 Gla residues. Here we describe the solution structure of the Ca(2+)-free Gla-EGF domain pair of factor x which reveals a striking difference between the Ca(2+)-free and Ca(2+)-loaded forms. In the Ca(2+)-free form Gla residues are exposed to solvent and Phe 4, Leu 5 and Val 8 form a hydrophobic cluster in the interior of the domain. In the Ca(2+)-loaded form Gla residues ligate Ca2+ in the core of the domain pushing the side-chains of the three hydrophobic residues into the solvent. We propose that the Ca(2+)-induced exposure of hydrophobic side chains is crucial for membrane binding of Gla-containing coagulation proteins.