6v08

Crystal structure of human recombinant Beta-2 glycoprotein I (hrB2GPI)

spinqualitylabelsall models 6v08, resolution 2.58Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6v08 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.58Å Ligands: BMA, MAN, NAG, SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function APOH_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 PubMed beta2-glycoprotein I (beta2GPI) is an abundant plasma protein displaying phospholipid-binding properties. Because it binds phospholipids, it is a target of antiphospholipid antibodies (aPLs) in antiphospholipid syndrome (APS), a life-threatening autoimmune thrombotic disease. Indeed, aPLs prefer membrane-bound beta2GPI to that in solution. beta2GPI exists in two almost equally populated redox states: oxidized, in which all the disulfide bonds are formed, and reduced, in which one or more disulfide bonds are broken. Furthermore, beta2GPI can adopt multiple conformations (i.e. J-elongated, S-twisted, and O-circular). While strong evidence indicates that the J-form is the structure bound to aPLs, which conformation exists and predominates in solution remains controversial, and so is the conformational pathway leading to the bound state. Here, we report that human recombinant beta2GPI purified under native conditions is oxidized. Moreover, under physiological pH and salt concentrations, this oxidized form adopts a J-elongated, flexible conformation, not circular nor twisted, in which the N-terminal domain I (DI) and the C-terminal domain V (DV) are exposed to the solvent. Consistent with this model, binding kinetics and mutagenesis experiments revealed that in solution the J-form interacts with negatively charged liposomes and with MBB2, a monoclonal anti-DI antibody that recapitulates most of the features of pathogenic aPLs. We conclude that the preferential binding of aPLs to phospholipid-bound beta2GPI arises from the ability of its pre-existing J-form to accumulate on the membranes, thereby offering an ideal environment for aPL binding. We propose that targeting the J-form of beta2GPI may provide a strategy to block pathogenic aPLs in APS. The J-elongated conformation of beta2-glycoprotein I predominates in solution: Implications for our understanding of antiphospholipid syndrome.,Ruben EA, Planer W, Chinnaraj M, Chen Z, Zuo X, Pengo V, De Filippis V, Alluri RK, McCrae KR, Macor P, Tedesco F, Pozzi N J Biol Chem. 2020 Jun 9. pii: RA120.013939. doi: 10.1074/jbc.RA120.013939. PMID:32518155 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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