Plasmin cleavage of β2-glycoprotein I alters its structure and ability to bind to pathogenic antibodies
Bibliographic record
Abstract
BACKGROUND: β2-Glycoprotein I (β2GPI) is the main autoantigenic target of antiphospholipid syndrome, with antibodies leading to clinical manifestations. There are 2 known structural isomers of β2GPI: a J shape and a circular shape. The transition between these structures is incompletely understood, with the functional implications unknown. β2GPI is a substrate of the protease plasmin, which cleaves within the fifth domain of β2GPI, leading to altered cellular binding. Very little is currently known regarding the structure and function of this protein variant. We present the first comprehensive structural characterization of plasmin-clipped β2GPI and the associated implications for pathogenic antibody binding to this protein. AIM: To determine if cleavage of B2GPI by plasmin triggers structural change, and what this change may mean for antibody reactivity. METHODS: β2GPI was purified using an adapted acid-free process from healthy control plasma and cleaved with plasmin. Cleavage was confirmed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Structural characterization was undertaken using dynamic light scattering, small-angle X-ray scattering, ion mobility mass spectrometry, and molecular dynamics simulation. Activity was tested using inhibition of β2GPI enzyme-linked immunosorbent assays with patient samples and cleaved β2GPI in the fluid phase and cellular binding by flow cytometry using human umbilical vein endothelial cells. RESULTS: Dynamic light scattering revealed a significantly smaller hydrodynamic radius for plasmin-clipped β2GPI (P = .0043). Small-angle X-ray scattering and molecular dynamics analysis indicated a novel S-like structure of β2GPI only present in the plasmin-clipped sample, while ion mobility mass spectrometry showed different structure distributions in plasmin-clipped compared with nonclipped β2GPI. The increased binding of autoantibodies was shown for plasmin-clipped β2GPI (P = .056), implying a greater exposure of pathogenic epitopes following cleavage. CONCLUSION: Cleavage of β2GPI by plasmin results in the production of a unique S-shaped structural conformation and higher patient antibody binding. This novel structure may increase the production of antibodies and explain the loss of binding to phospholipids described previously for plasmin-clipped β2GPI.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".