Pinpointing The Structural Dynamics of Plasminogen Activator Inhibitor -1 upon binding to Heparin using Hydrogen/Deuterium Exchange Mass Spectrometry
Bibliographic record
Abstract
The native conformation of plasminogen activator inhibitor (PAI-1) is an active metastable structure that transforms spontaneously to an inactive latent form within 1-2 hrs under physiological conditions. PAI-1 is a key player to regulate the activation of fibrinolysis, with broad influence effects on inflammation, hemostasis, tissue remodeling, and wound healing 1 . The binding of endogenous cofactor vitronectin to PAI-1 causes delaying in the transition to the latent state and significantly boosts the protein's thermal stability 2 . This binding helps to extend PAI-1 half-life and delay its latency transition thus controlling the stability of the active form. Previous studies have suggested that low molecular weight heparin alters the levels of circulating PAI-1 and enhances endogenous fibrinolysis 3 . However, the intrinsic dynamics of this binding are not completely understood. We have used hydrogen/deuterium exchange mass spectrometry to elucidate the structural dynamics of PAI-1 and heparin binding. Heparin binding to PAI-1 induces significant attenuation of deuterium uptake in PAI-1. The strongest protection against isotopic exchange is observed in the lower half of PAI-1. Peptides covering the heparin binding interface are shielded from the solvent and show a slow exchange rate. In addition, we observed a moderate effect on the peptides remote from the heparin binding site. These peptides are topographically connected in a circle-like shape around the vertical axis of the protein structure. Our findings reveal that heparin may contribute to the localization of PAI-1 at specific sites, hence involved in the regulation of plasminogen activation and its functional stability.
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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 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| 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".