International Immunology, Vol. 12, No. 8, 1183-1192,
August 2000
© 2000 Japanese Society for Immunology
Proteolytic cleavage of ß2-glycoprotein I: reduction of antigenicity and the structural relationship
1 Department of Cell Chemistry, Institute of Cellular and Molecular Biology, Okayama University Medical School, 2-5-1 Shikata-cho, Okayama 700-8558, Japan
2 Department of Medicine II, Hokkaido University School of Medicine, Sapporo 060-8638, Japan
3 Biomedical Computation Center, Osaka Medical College, Takatsuki 569-8686, Japan
4 Department of Pathology, Ball Memorial Hospital, Muncie, IN 47303, USA
Correspondence to: E. Matsuura
Binding of ß2-glycoprotein I (ß2-GPI)-dependent anticardiolipin antibodies (aCL) derived from antiphospholipid syndrome (APS) is significantly reduced in aCL ELISA due to loss of the phospholipid (PL) binding property of ß2-GPI by plasmin treatment. In the present study, the treatment generated a nicked form of ß2-GPI and resulted in loss of antigenicity for the autoantibodies detected in ELISA, using an ß2-GPI directly adsorbed polyoxygenated carboxylated plate, the assay system of which was not related to PL binding. The nicked form bound to neither Cu2+-oxidized low-density lipoprotein (oxLDL) nor to ß2-GPI-specific lipid ligands isolated from oxLDL, the result being a complete loss of subsequent binding of anti-ß2-GPI autoantibodies. The conformational change in the nicked domain V was predicted from its intact structure determined by an X-ray analysis (implemented in Protein Data Bank: 1C1Z), molecular modeling and epitope mapping of a monoclonal anti-ß2-GPI antibody, i.e. Cof-18, which recognizes the related structure. The analysis revealed that novel hydrophobic and electrostatic interactions appeared in domain V after the cleavage, thereby affecting the PL binding of ß2-GPI. Such a conformational change may have important implications for exposure of cryptic epitopes located in the domains such as domain IV.
Keywords: antiphospholipid syndrome, anti-ß2-glycoprotein I antibodies, epitope mapping, plasmin, structure
Transmitting editor: K. Okumura
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