title: Domain V of beta2-glycoprotein I binds factor XI/XIa and is cleaved at Lys317-Thr318.
abstract: The fifth domain (DV) of beta2-glycoprotein I (beta2GPI) is important for binding a number of ligands including phospholipids and factor XI (FXI). Beta2GPI is proteolytically cleaved in DV by plasmin but not by thrombin, VIIa, tissue plasminogen activator, or uPA. Following proteolytic cleavage of DV by plasmin, beta2GPI retains binding to FXI but not to phospholipids. Native beta2GPI, but not cleaved beta2GPI, 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 beta2GPI using site-directed mutagenesis. We show that the positively charged residues Lys284, Lys286, and Lys287 in DV are essential for the interaction of beta2GPI with FXI/FXIa. We also demonstrate that FXIa proteolytically cleaves beta2GPI at Lys317-Thr318 in DV. Thus, FXIa cleavage of beta2GPI in vivo during thrombus formation may accelerate FXI activation by decreasing the inhibitory effect of beta2GPI.
authors.affiliation: Department of Medicine, Department of Immunology, Allergy & Infectious Diseases, St. George Hospital, University of New South Wales, Sydney, New South Wales 2217, Australia.
authors.forename: Tong
authors.initials: T
authors.lastname: Shi
authors.forename: Bill
authors.initials: B
authors.lastname: Giannakopoulos
authors.forename: G Michael
authors.initials: GM
authors.lastname: Iverson
authors.forename: Keith A
authors.initials: KA
authors.lastname: Cockerill
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Linnik
authors.forename: Steven A
authors.initials: SA
authors.lastname: Krilis
mesh_terms: D001665:Binding Sites; D005172:Factor XI / Q000378:metabolism*; D015945:Factor XIa / Q000378:metabolism*; D005341:Fibrinolysin / Q000378:metabolism; D006023:Glycoproteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D010447:Peptide Hydrolases / Q000378:metabolism; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D013912:Threonine / Q000378:metabolism*; D013917:Thrombin / Q000378:metabolism; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000378:metabolism; D053482:beta 2-Glycoprotein I
chemical_list: D006023:Glycoproteins; D053482:beta 2-Glycoprotein I; D013912:Threonine; D005172:Factor XI; D010447:Peptide Hydrolases; D015945:Factor XIa; D013917:Thrombin; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin; D008239:Lysine