Abstract 110: The Separation of Serum Amyloid A from HDL is Mediated by Heparan Sulfate Through Histidine Dependent Interactions: HDL Function is Enhanced but Amyloid-Fibrils may be the “Price to Pay”¼
Bibliographic record
Abstract
Serum amyloid A (SAA) is an acute-phase protein that circulates bound to high density lipoprotein (HDL) and can influence HDL function as part of a poorly understood defense re-sponse to tissue trauma or infection. We have previously demonstrated that under mildly acidic pH the glycosaminoglycans, heparan sulfate (HS) and heparin can interact with HDL-SAA and cause SAA to dissociate from HDL. This remodeling improves HDL functionality but also predisposes SAA to form AA-amyloid fibrils. In this study we explore some potential pathophysiological conditions in vitro that could influence this HS/HDL-SAA remodeling process and the fate of SAA in vivo. SAA’s binding affinity for heparin was found to be enhanced by acidic pH and low concentrations of urea. The heparin dependent remodeling of HDL-SAA was promoted by the partial denaturation of HDL-SAA. Moreover, HDL-SAA remodeling was observed to follow a strict SAA:heparin stoichiometry and could be partially inhibited with a short heparin oligosaccharide of 8-sugar units. Evidence is also presented that once dissociated from HDL, SAA requires additional time to organize into Triton x-100 resistant amyloid-like structures. Circular dichroism spectroscopic analysis and in silico modeling of SAA’s ionizable residues highlights the importance of the histidine-36 within a highly conserved, pH-sensitive HS-binding site (HSBS-pH). A peptide containing the HSBS-pH sequence was demonstrated to have AA-amyloid seeding activity in a cell culture system. The recent determination of the 3D structure for human SAA1.1 has allowed the opportunity to re-assess and validate the HS/heparin binding sequences that had previously been identified biochemically with short synthetic peptides. We postulate that the dissociation of SAA from HDL takes place during the retro-endocytosis of HDL-SAA and is an important aspect of SAA function not previously appreciated.
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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) | 0.007 | 0.002 |
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".