Protein S (PS) is a cofactor for activated protein C (APC), which inactivates coagulation factors (F) Va and VIIIa. Deficiency of protein C or PS is associated with risk of thrombosis. We found that PS also has APC-independent anticoagulant activity (PS-direct) and directly inhibits thrombin generated by FXa/FVa (prothrombinase complex). Here we report that PS contains Zn 2+ that is required for PS-direct and that is lost during certain purification procedures. Immunoaffinity-purified PS contained 1.4 ± 0.6 Zn 2+ /mol, whereas MonoQ-purified and commercial PS contained 0.15 ± 0.15 Zn 2+ /mol. This may explain the controversy regarding the validity of PS-direct. Zn 2+ content correlated positively with PS-direct in prothrombinase assays and clotting assays, but APC-cofactor activity of PS was independent of Zn 2+ content. PS-direct and Zn 2+ were restored to inactive PS under mildly denaturing conditions. Conversely, o -phenanthroline reversibly impaired the PS-direct of active PS. Zn 2+ -containing PS bound FXa more efficiently ( K d app =9.3 nM) than Zn 2+ -deficient PS ( K d app =110 nM). PS bound TFPI efficiently, independently of Zn 2+ content ( K d app =21 nM). Antibodies that block PS-direct preferentially recognized Zn 2+ -containing PS, suggesting conformation differences at or near the interface of 2 laminin G-like domains near the PS C terminus. Thus, Zn 2+ is required for PS-direct and efficient FXa binding and may play a role in stabilizing PS conformation.—Heeb, M. J., Prashun, D., Griffin, J. H., Bouma, B. N. Plasma protein S contains zinc essential for efficient activated protein C-independent anticoagulant activity and binding to factor Xa, but not for efficient binding to tissue factor pathway inhibitor.
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Plasma protein S contains zinc essential for efficient activated protein C-independent anticoagulant activity and binding to factor Xa, but not for efficient binding to tissue factor pathway inhibitor
Heeb, Mary J.; Prashun, Duane; Griffin, John H.; Bouma, Bonno N.
Follow The FASEB Journal
, Volume 23 (7): 2244
Fed of American Socs for Experimental Biology – Jul 1, 2009
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