The J-shape of β2GPI reveals a cryptic discontinuous epitope across domains I and II
Beta-2-Glycoprotein I is the main target for pathogenic antiphospholipid syndrome autoantibodies. It can adopt several conformations, including an O-shape and two more linear J- and S-shapes. The in vivo existence of the O-shape is debated, and doubt remains pertaining to the pathogenic impact of ea...
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Elsevier
2025-12-01
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| Series: | Journal of Structural Biology: X |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2590152425000169 |
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| author | C.J. Lalaurie M. Kulke N. Geist M. Delcea P.A. Dalby T.C.R. McDonnell |
| author_facet | C.J. Lalaurie M. Kulke N. Geist M. Delcea P.A. Dalby T.C.R. McDonnell |
| author_sort | C.J. Lalaurie |
| collection | DOAJ |
| description | Beta-2-Glycoprotein I is the main target for pathogenic antiphospholipid syndrome autoantibodies. It can adopt several conformations, including an O-shape and two more linear J- and S-shapes. The in vivo existence of the O-shape is debated, and doubt remains pertaining to the pathogenic impact of each shape. Studies have shown that APS antibodies react weakly with the O-shape and bind to the linear shapes due to the exposure of a cryptic epitope in the 1st domain. How the protein transitions from O-shape to the linear shapes remains unknown. While the main epitope is widely recognised as the R39-R43 peptide, there is evidence pointing to a discontinuous epitope across domains I and II (DI & DII). We used molecular dynamics simulations to examine the potential pathways of conformational shift from the O-shape to the open forms, and the impact of plasmin clipping on these pathways. Through these studies, starting in a theorised O-shape, we identified that peptides R39-R43, T50-N56 and R63-F67 become more exposed and have increased stability in the J- and S-shapes relative to the O-shape. These changes are likely due to a shift in DII of the T106-G109 loop, which twists to form contacts with the DI K33-Y36 loop. The R39-R43 peptide is brought closer to R63-F67 suggesting a more complex DI epitope than previously theorised. These effects were observed in the wild type and plasmin clipped model, with the effect being larger in the latter. These results are in good agreement with the increased antibody binding observed experimentally for the clipped protein. We therefore suggest that we have been able to identify the structural mechanism at the residue level which results in increased antibody binding in the J-Shape, and specifically in the clipped protein. |
| format | Article |
| id | doaj-art-c22ccd3e0e584e41b0ece61b203452f0 |
| institution | Kabale University |
| issn | 2590-1524 |
| language | English |
| publishDate | 2025-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Structural Biology: X |
| spelling | doaj-art-c22ccd3e0e584e41b0ece61b203452f02025-08-23T04:49:03ZengElsevierJournal of Structural Biology: X2590-15242025-12-011210013510.1016/j.yjsbx.2025.100135The J-shape of β2GPI reveals a cryptic discontinuous epitope across domains I and IIC.J. Lalaurie0M. Kulke1N. Geist2M. Delcea3P.A. Dalby4T.C.R. McDonnell5Division of Medicine, Rayne Building, 5 University Street, University College London WC1E 6JF London, United KingdomTheoretical Biophysics, Ernst-Otto-Fischer-Str. 8, 85748 Garching b., Technical University Munich, Munich, GermanyBiophysical Chemistry, Felix Hausdorff-Strasse 4, 17487, University of Greifswald, Greifswald, GermanyBiophysical Chemistry, Felix Hausdorff-Strasse 4, 17487, University of Greifswald, Greifswald, GermanyDepartment of Biochemical Engineering, Bernard Katz, Gower Street, University College London WC1E 6BT London, United KingdomDivision of Medicine, Rayne Building, 5 University Street, University College London WC1E 6JF London, United KingdomBeta-2-Glycoprotein I is the main target for pathogenic antiphospholipid syndrome autoantibodies. It can adopt several conformations, including an O-shape and two more linear J- and S-shapes. The in vivo existence of the O-shape is debated, and doubt remains pertaining to the pathogenic impact of each shape. Studies have shown that APS antibodies react weakly with the O-shape and bind to the linear shapes due to the exposure of a cryptic epitope in the 1st domain. How the protein transitions from O-shape to the linear shapes remains unknown. While the main epitope is widely recognised as the R39-R43 peptide, there is evidence pointing to a discontinuous epitope across domains I and II (DI & DII). We used molecular dynamics simulations to examine the potential pathways of conformational shift from the O-shape to the open forms, and the impact of plasmin clipping on these pathways. Through these studies, starting in a theorised O-shape, we identified that peptides R39-R43, T50-N56 and R63-F67 become more exposed and have increased stability in the J- and S-shapes relative to the O-shape. These changes are likely due to a shift in DII of the T106-G109 loop, which twists to form contacts with the DI K33-Y36 loop. The R39-R43 peptide is brought closer to R63-F67 suggesting a more complex DI epitope than previously theorised. These effects were observed in the wild type and plasmin clipped model, with the effect being larger in the latter. These results are in good agreement with the increased antibody binding observed experimentally for the clipped protein. We therefore suggest that we have been able to identify the structural mechanism at the residue level which results in increased antibody binding in the J-Shape, and specifically in the clipped protein.http://www.sciencedirect.com/science/article/pii/S2590152425000169Structural biologyMolecular DynamicsAuto-antigen epitopeAPSBeta-2-glycoprotein I |
| spellingShingle | C.J. Lalaurie M. Kulke N. Geist M. Delcea P.A. Dalby T.C.R. McDonnell The J-shape of β2GPI reveals a cryptic discontinuous epitope across domains I and II Journal of Structural Biology: X Structural biology Molecular Dynamics Auto-antigen epitope APS Beta-2-glycoprotein I |
| title | The J-shape of β2GPI reveals a cryptic discontinuous epitope across domains I and II |
| title_full | The J-shape of β2GPI reveals a cryptic discontinuous epitope across domains I and II |
| title_fullStr | The J-shape of β2GPI reveals a cryptic discontinuous epitope across domains I and II |
| title_full_unstemmed | The J-shape of β2GPI reveals a cryptic discontinuous epitope across domains I and II |
| title_short | The J-shape of β2GPI reveals a cryptic discontinuous epitope across domains I and II |
| title_sort | j shape of β2gpi reveals a cryptic discontinuous epitope across domains i and ii |
| topic | Structural biology Molecular Dynamics Auto-antigen epitope APS Beta-2-glycoprotein I |
| url | http://www.sciencedirect.com/science/article/pii/S2590152425000169 |
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