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 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.
Ohkubo
Y Zenmei
YZ
Department of Biochemistry, Beckman Institute and Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
Tajkhorshid
Emad
E
D000595:Amino Acid Sequence; D001779:Blood Coagulation Factors / Q000737:chemistry* / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002462:Cell Membrane / Q000201:enzymology / Q000378:metabolism; D016208:Databases, Factual; D015942:Factor VIIa / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D012697:Serine Endopeptidases / Q000737:chemistry* / Q000378:metabolism*; D013925:Thromboplastin / Q000737:chemistry / Q000378:metabolism
D001779:Blood Coagulation Factors; D013925:Thromboplastin; D012697:Serine Endopeptidases; D015942:Factor VIIa; D002118:Calcium