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| Title | Cryo-EM structure and functional basis of prothrombin recognition by a type I antiprothrombin antiphospholipid antibody. |
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| Journal, issue, pages | Blood, Vol. 143, Issue 19, Page 2005-2011, Year 2024 |
| Publish date | May 9, 2024 |
 Authors | Suresh Kumar / Brock Summers / Kathrine Basore / Vittorio Pengo / Robert Flaumenhaft / Nicola Pozzi /   |
| PubMed Abstract | Antiprothrombin antibodies are found in antiphospholipid patients, but how they interact with prothrombin remains elusive. Prothrombin adopts closed and open forms. We recently discovered type I and ...Antiprothrombin antibodies are found in antiphospholipid patients, but how they interact with prothrombin remains elusive. Prothrombin adopts closed and open forms. We recently discovered type I and type II antibodies and proposed that type I recognizes the open form. In this study, we report the discovery and structural and functional characterization in human plasma of a type I antibody, POmAb (prothrombin open monoclonal antibody). Using surface plasmon resonance and single-molecule spectroscopy, we show that POmAb interacts with kringle-1 of prothrombin, shifting the equilibrium toward the open form. Using single-particle cryogenic electron microscopy (cryo-EM), we establish that the epitope targeted by POmAb is in kringle-1, comprising an extended binding interface centered at residues R90-Y93. The 3.2-Å cryo-EM structure of the complex reveals that the epitope overlaps with the position occupied by the protease domain of prothrombin in the closed state, explaining the exclusive binding of POmAb to the open form. In human plasma, POmAb prolongs phospholipid-initiated and diluted Russell's viper venom clotting time, which could be partly rescued by excess phospholipids, indicating POmAb is an anticoagulant but exerts a weak lupus anticoagulant effect. These studies reveal the structural basis of prothrombin recognition by a type I antiphospholipid antibody and uncover an exciting new strategy to achieve anticoagulation in human plasma. |
 External links | Blood / PubMed:38437497 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 3.2 Å |
| Structure data | EMDB-42185, PDB-8uf7: |
| Source |
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 Keywords | BLOOD CLOTTING / Autoimmunity / Thrombosis / Complex / Immunoglobulin / Coagulation factor / Anticoagulation / Inhibitor |
mus musculus (house mouse)
homo sapiens (human)