Structural analyses of apolipoprotein A-IV polymorphisms Q360H and T347S elucidate the inhibitory effect against thrombosis
Bibliographic record
Abstract
Apolipoprotein A-IV (apoA-IV) is an abundant lipid-binding protein in blood plasma. We previously reported that apoA-IV, as an endogenous inhibitor, competitively binds platelet α IIb β 3 integrin from its N-terminal residues, reducing the potential risk of thrombosis. This study aims to investigate how the apoA-IV Q360H and apoA-IV T347S mutations affect the structure and function of apoA-IV. These mutations are linked to increased risk of cardiovascular diseases because of multiple single-nucleotide polymorphisms in the C-terminal region of apoA-IV. We postulate that the structural hindrance caused by the C-terminal motifs may impede the binding of apoA-IV to platelets at its N-terminal binding site. However, the mechanistic impact of Q360H and T347S polymorphisms on this intermolecular interaction and their potential contribution to the development of cardiovascular disease have not been adequately investigated. To address this, recombinant forms of human apoA-IV WT , apoA-IV Q360H , and apoA-IV T347S variants were produced, and the structural stability, dimerization, and molecular dynamics of the C terminus were examined utilizing biophysical techniques, including fluorescence anisotropy, fluorescence spectrophotometry, circular dichroism, and biolayer interferometry methods. Our results showed a decreased fraction of α -helix structure in apoA-IV Q360H and apoA-IV T347S compared with the WT, and the inhibitory effect of dimerized apoA-IV on platelet aggregation was reduced in apoA-IV Q360H and apoA-IV T347S variants. Binding kinetics of examined apoA-IV polymorphisms to platelet α IIb β 3 suggest a potential mechanism for increased risk of cardiovascular diseases in individuals with apoA-IV Q360H and apoA-IV T347S polymorphisms.
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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".