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.
Sunnerhagen
M
M
Chemical Center, Lund University, Sweden.
Forsén
S
S
Hoffrén
A M
AM
Drakenberg
T
T
Teleman
O
O
Stenflo
J
J
D015055:1-Carboxyglutamic Acid / Q000737:chemistry*; D000595:Amino Acid Sequence; D000925:Anticoagulants / Q000737:chemistry; D001779:Blood Coagulation Factors / Q000235:genetics; D002118:Calcium / Q000737:chemistry; D002462:Cell Membrane / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000737:chemistry / Q000235:genetics; D005170:Factor X / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment
D000925:Anticoagulants; D001779:Blood Coagulation Factors; D015055:1-Carboxyglutamic Acid; D004815:Epidermal Growth Factor; D005170:Factor X; D002118:Calcium