Characterizing Y532H disease‐causing mutation and N‐terminal domains of the human Wilson protein
Bibliographic record
Abstract
The human Wilson protein (ATP7B) is a copper transporting ATPase that is involved in copper homeostasis. Mutations in the gene coding for this protein leads to Wilson Disease (WD), a hepatological disorder characterized by impaired excretion of copper in bile. We characterized Y532H disease‐causing mutant, and its interaction with a copper chaperone, HAH1 (also known as Atox1). We examined structural effects of Y532H mutation in domains 5 and 6 wild type construct of ATP7B. It was found that the mutation alters the solubility of the expressed protein, decrease overall protein stability as observed by circular dichroism (CD) spectroscopy and does not interfere with copper binding. The 15 N HSQC experiments by NMR reveal an essentially folded protein, a phenomenon also supported by CD experiments. The amide chemical shifts are highly similar between the wild type and mutant WLN5‐6 for the domain 6 (G80‐Q149), as shown by chemical shift variation (CSV) data, and the most affected amino residues are those spatially close to mutation which includes Q4‐F7, K47‐H(Y)48 (mutation) and V52‐I53. In conclusion, the Y532H mutation is perceived to perturb the hydrogen bond network in domain 5, which is critical for a compact structure, thus inducing motions on the side chains and break the linkage between two domains, causing inter‐domain motion and structural heterogeneity, which is absent in the wild type. (This work was supported by Wilson's disease Association grant)
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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".