STRUCTURE OF THE CA2+-FREE GLA DOMAIN SHEDS LIGHT ON MEMBRANE-BINDING OF BLOOD-COAGULATION PROTEINS

Reversible membrane binding of gamma-carboxyglutamic acid (Gla)-containing coagulation factors requires Ca2+-binding to 10-12 Gla residues. Here we describe the solution structure of the Ca2+-free Gla-EGF domain pair of factor X which reveals a striking difference between the Ca2+-free and Ca2+-loaded forms. In the Ca2+-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 Ca2+-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 Ca2+-induced exposure of hydrophobic side chains is crucial for membrane binding of Gla-containing coagulation proteins.