DOMAIN V OF BETA2-GLYCOPROTEIN I BINDS FACTOR XI/XIa AND IS CLEAVED AT Lys317-Thr318

T. Shi, B. Giannakopoulos, GM Iverson, KA Cockerill, MD Linnik, SA Krilis

The 5th domain (DV) of beta2-glycoprotein I (B2GPI) is important for binding a number of ligands, including phospholipids and factor XI (FXI). B2GPI is proteolytically cleaved in DV by plasmin but not by thrombin, VIIa, TPA or uPA. Following proteolytic cleavage of DV by plasmin B2GPI retains binding to FXI but not to phospholipids. Native B2GPI, but not cleaved B2GPI, inhibits activation of FXI by thrombin and factor XIIa, attenuating a positive feedback mechanism for additional thrombin generation. In this report we have defined the FXI/FXIa binding site on B2GPI using site-directed mutagenesis. We show that the positively charged residues Lys284, Lys286 and Lys287 in DV are essential for the interaction of B2GPI at Lys317-Thr318 in DV. Thus, FXIa cleavage of B2GPI in vivo during thrombus formation may accelerate FXI activation by decreasing the inhibitory effect of B2GPI.

Published in
Journal of Biological Chemistry
2005 Volume 280: pp. 907-912