Domain v of β2-Glycoprotein I binds factor XI/XIa and is cleaved at Lys317-Thr318

The fifth domain (DV) of beta(2)-glycoprotein I (beta(2)GPI) is important for binding a number of ligands including phospholipids and factor XI (FXI). beta(2)GPI is proteolytically cleaved in DV by plasmin but not by thrombin, VIIa, tissue plasminogen activator, or uPA. Following proteolytic cleavage of DV by plasmin, beta(2)GPI retains binding to FXI but not to phospholipids. Native beta(2)GPI, but not cleaved beta(2)GPI, 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 beta(2)GPI using site-directed mutagenesis. We show that the positively charged residues Lys(284), Lys(286), and Lys(287) in DV are essential for the interaction of beta(2)GPI with FXI/FXIa. We also demonstrate that FXIa proteolytically cleaves beta(2)GPI at Lys(317)- Thr(318) in DV. Thus, FXIa cleavage of beta(2)GPI in vivo during thrombus formation may accelerate FXI activation by decreasing the inhibitory effect of beta(2)GPI.