Structural-functional relationships in the human thrombin A-chain
Bibliographic record
Abstract
Thrombin is the terminal protease in the coagulation cascade and plays a pivotal role in haemostasis, affecting both amplification and down-regulation of coagulation. Although prothrombin is one of the most widely studied enzymes in biology, the role of the thrombin A-chain region has been neglected in comparison to the other domains. While originally considered to be simply an activation remnant with little physiological function, mutations in the prothrombin A-chain region lead to bleeding disorders. There is evidence that the thrombin A-chain may play a role as an allosteric effector in enzymatic reactions and may also represent a structural scaffold to stabilize the protease domain; however, the exact role(s) of the A-chain remain to be elucidated. In this thesis, the roles of the A-chain region in prothrombin folding and activation, thrombin Ca²⁺⁺ binding, enzyme stability and function were investigated. The results from this study suggest that the A-chain region is not required for prothrombin folding and secretion out of the cells; however, the A-chain is required for prothrombin activation. In an independent study using x-ray crystallographic techniques, NMR and activity assays, no evidence of a Ca²⁺⁺ binding site was found in the thrombin A-chain or elsewhere in the thrombin molecule. During prothrombin activation, nascent thrombin undergoes autolysis of a 13-residue N-terminal peptide of the A-chain to produce α-thrombin. Nascent thrombin and α-thrombin were compared to assess the effects of the A13 peptide. Contrary to expectation, autolysis of the A13 peptide at the N-terminus of the thrombin A-chain was very slow, with a half life of 46 minutes. Investigation of whether retention of this peptide affected thrombin structure and activity revealed that nascent thrombin was significantly different than α-thrombin in terms of 1) chromogenic activity and fibrinogen clotting activity, 2) thermal stability, 3) heparin binding and 4) inhibition by antithrombin. These studies further our knowledge of the roles the A-chain plays in the zymogen prothrombin and protease thrombin, and demonstrate that the A-chain A13 peptide of nascent thrombin may be a procoagulant stabilizer of thrombin in coagulation.
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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) | 0.002 | 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".