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Journal Article
Research Support, Non-U.S. Gov't
Molecular mapping of α-thrombin (αT)/β2-glycoprotein I (β2GpI) interaction reveals how β2GpI affects αT functions.
Biochemical Journal 2016 December 16
β2-Glycoprotein I (β2GpI) is the major autoantigen in the antiphospholipid syndrome, a thrombotic autoimmune disease. Nonetheless, the physiological role of β2GpI is still unclear. In a recent work, we have shown that β2GpI selectively inhibits the procoagulant functions of human α-thrombin (αT; i.e. prolongs fibrin clotting time, tc , and inhibits αT-induced platelet aggregation) without affecting the unique anticoagulant activity of the protease, i.e. the proteolytic generation of the anticoagulant protein C (PC) from the PC zymogen, which interacts with αT exclusively at the protease catalytic site. Here, we used several different biochemical/biophysical techniques and molecular probes for mapping the binding sites in the αT-β2GpI complex. Our results indicate that αT exploits the highly electropositive exosite-II, which is also responsible for anchoring αT on the platelet GpIbα (platelet receptor glycoprotein Ibα) receptor, for binding to a continuous negative region on β2GpI structure, spanning domain IV and (part of) domain V, whereas the protease active site and exosite-I (i.e. the fibrinogen-binding site) remain accessible for substrate/ligand binding. Furthermore, we provided evidence that the apparent increase in tc , previously observed with β2GpI, is more likely caused by alteration in the ensuing fibrin structure rather than by the inhibition of fibrinogen hydrolysis. Finally, we produced a theoretical docking model of αT-β2GpI interaction, which was in agreement with the experimental results. Altogether, these findings help to understand how β2GpI affects αT interactions and suggest that β2GpI may function as a scavenger of αT for binding to the GpIbα receptor, thus impairing platelet aggregation while enabling normal cleavage of fibrinogen and PC.
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