Abstract 14: Characterization of the Oxidized Phospholipid Modification of Apolipoprotein(a) Kringle KIV10: Insights Into the Site of OxPC Addition
Bibliographic record
Abstract
Elevated plasma levels of lipoprotein(a) (Lp(a)) are an independent and causal risk factor for coronary heart disease and aortic valve stenosis. Lp(a) consists of a low density lipoprotein (LDL)-like particle covalently linked to the unique glycoprotein apolipoprotein(a) (apo(a)). We have shown that apo(a) contains a covalent oxidized phosphocholine (oxPC) adduct on the KIV 10 domain, and that perturbation of the strong lysine binding site (LBS) in this kringle results in a lack of covalent oxPC addition. We have implicated this modification in proinflammatory processes, such as the ability of apo(a) to induce interleukin-8 expression in macrophages. Apo(a) from Old World monkeys and apes lacks covalent oxPC modification and contains mutations in KIV 10 , some of which impact the LBS. To identify the amino acids in human apo(a) that are covalently modified by oxPC, we mutagenized a KIV 10 KV di-kringle apo(a) that contains covalent oxPC modification. We mutated to alanine all residues that are either substituted in primate apo(a) or that can act as acceptors for covalent oxPC addition. The resulting variants were then subjected to immunoblotting analysis with E06, an IgM antibody that binds to oxPC, and assessment of lysine-binding ability using affinity chromatography. Mutation of His33 to Ala abolishes oxPC modification of apo(a) while retaining the lysine binding ability of KIV 10 . Thus, we have identified the long-sought location of the oxPC modification of apo(a). Molecular dynamic simulations of the oxPC-deficient mutant show no gross changes in the structure of KIV 10 , in contrast to mutations that abolish both lysine binding ability and oxPC addition that result in a collapsed lysine binding pocket. Using mass spectrometry, we have also identified noncovalently-associated oxPC present on apo(a). Interestingly, the abundance of these species appears to be reduced in the apo(a) variant containing a mutation in the strong lysine binding site in KIV 10 . Our findings allow the ability to assess the contributions to pathogenesis of the strong lysine binding site and oxPC modification of apo(a) kringle IV type 10 independently, and thus will enhance our understanding of the mechanisms by which Lp(a) contributes to atherothrombotic diseases.
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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 | 0.001 |
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".