3op8
Crystal structure of the domain V from beta2-glycoprotein I
Structural highlights
FunctionAPOH_HUMAN Binds to various kinds of negatively charged substances such as heparin, phospholipids, and dextran sulfate. May prevent activation of the intrinsic blood coagulation cascade by binding to phospholipids on the surface of damaged cells. Publication Abstract from PubMedBACKGROUND: beta2GPI is a major antigen for autoantibodies associated with antiphospholipid syndrome (APS), an autoimmune disease characterized by thrombosis and recurrent pregnancy loss. Only the dimeric form of beta2GPI generated by anti-beta2GPI antibodies is pathologically important, in contrast to monomeric beta2GPI which is abundant in plasma. PRINCIPAL FINDINGS: We created a dimeric inhibitor, A1-A1, to selectively target beta2GPI in beta2GPI/antibody complexes. To make this inhibitor, we isolated the first ligand-binding module from ApoER2 (A1) and connected two A1 modules with a flexible linker. A1-A1 interferes with two pathologically important interactions in APS, the binding of beta2GPI/antibody complexes with anionic phospholipids and ApoER2. We compared the efficiency of A1-A1 to monomeric A1 for inhibition of the binding of beta2GPI/antibody complexes to anionic phospholipids. We tested the inhibition of beta2GPI present in human serum, beta2GPI purified from human plasma and the individual domain V of beta2GPI. We demonstrated that when beta2GPI/antibody complexes are formed, A1-A1 is much more effective than A1 in inhibition of the binding of beta2GPI to cardiolipin, regardless of the source of beta2GPI. Similarly, A1-A1 strongly inhibits the binding of dimerized domain V of beta2GPI to cardiolipin compared to the monomeric A1 inhibitor. In the absence of anti-beta2GPI antibodies, both A1-A1 and A1 only weakly inhibit the binding of pathologically inactive monomeric beta2GPI to cardiolipin. CONCLUSIONS: Our results suggest that the approach of using a dimeric inhibitor to block beta2GPI in the pathological multivalent beta2GPI/antibody complexes holds significant promise. The novel inhibitor A1-A1 may be a starting point in the development of an effective therapeutic for antiphospholipid syndrome. A Novel Dimeric Inhibitor Targeting Beta2GPI in Beta2GPI/Antibody Complexes Implicated in Antiphospholipid Syndrome.,Kolyada A, Lee CJ, De Biasio A, Beglova N PLoS One. 2010 Dec 15;5(12):e15345. PMID:21179511[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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