Kinetics of competitive Cd2+ binding pathways: the realistic structure of intrinsically disordered, partially metallated metallothioneins
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Bibliographic record
Abstract
The 20-cysteine mammalian metallothioneins are considered to be central to the homeostatic control of the essential metals Zn(ii) and Cu(i) and, as part of their metal-loaded status, play a role in reversing oxidative stress. Native apo-MT does not adopt a well-known structural motif, being described as a random-coil or intrinsically-disordered. Conclusions reached from a combination of ESI-mass spectral charge states, As(iii) metallation of apo-MT at low pH, from molecular dynamic calculations and from metallation of the α-domain fragment, suggest that in fact the native apo-MT adopts a structure that is highly efficient towards metallation at physiological pH. The results in this paper show that the initial (M < 5) Cd(ii) metallation at physiological pH takes place to form structures based on isolated Cd(SCYS)4 units, beads. At pH 5, cysteine bridged Cd4(SCYS)11 clusters form. ESI-mass spectral profile of cysteine modification of apo-MT at physiological pH shows that it is folded, whereas in the presence of 3 M guandinium hydrochloride the apo-MT is unfolded. Stopped flow kinetic studies of the Cd(ii) metallation shows that the reaction is much slower for the unfolded vs. the folded apo-MT for formation of either beads or clusters. Metallation is also much slower for the formation of clusters than the formation of beads. These results are first to quantify the presence of structure in native apo-MT in terms of the critical metallation properties. The implications of this study suggest that oxidation of apo-MT due to ageing or other agent will negatively impact the metallation process for essential metals.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 it