Molecular mapping of α-thrombin (αT)/ß2-glycoprotein I (ß2GpI) interaction reveals how ß2GpI affects αT functions.
Biochem J
; 473(24): 4629-4650, 2016 12 15.
Article
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| MEDLINE
| ID: mdl-27760842
ABSTRACT
ß2-Glycoprotein I (ß2GpI) is the major autoantigen in the antiphospholipid syndrome, a thrombotic autoimmune disease. Nonetheless, the physiological role of ß2GpI is still unclear. In a recent work, we have shown that ß2GpI 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-ß2GpI 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 ß2GpI 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 ß2GpI, 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-ß2GpI interaction, which was in agreement with the experimental results. Altogether, these findings help to understand how ß2GpI affects αT interactions and suggest that ß2GpI 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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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Trombina
/
Beta 2 Glicoproteína I
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Biochem J
Año:
2016
Tipo del documento:
Article
País de afiliación:
Italia