The effect of Mg <sup>2+</sup> on Ca <sup>2+</sup> binding to cardiac troponin C in hypertrophic cardiomyopathy associated <scp> <i>TNNC1</i> </scp> variants
Bibliographic record
Abstract
Cardiac troponin C (cTnC) is the critical Ca 2+ ‐sensing component of the troponin complex. Binding of Ca 2+ to cTnC triggers a cascade of conformational changes within the myofilament that culminate in force production. Hypertrophic cardiomyopathy (HCM)‐associated TNNC1 variants generally induce a greater degree and duration of Ca 2+ binding, which may underly the hypertrophic phenotype. Regulation of contraction has long been thought to occur exclusively through Ca 2+ binding to site II of cTnC. However, work by several groups including ours suggest that Mg 2+ , which is several orders of magnitude more abundant in the cell than Ca 2+ , may compete for binding to the same cTnC regulatory site. We previously used isothermal titration calorimetry (ITC) to demonstrate that physiological concentrations of Mg 2+ may decrease site II Ca 2+ ‐binding in both N‐terminal and full‐length cTnC. Here, we explore the binding of Ca 2+ and Mg 2+ to cTnC harbouring a series of TNNC1 variants thought to be causal in HCM. ITC and thermodynamic integration (TI) simulations show that A8V, L29Q and A31S elevate the affinity for both Ca 2+ and Mg 2+ . Further, L48Q, Q50R and C84Y that are adjacent to the EF hand binding motif of site II have a more significant effect on affinity and the thermodynamics of the binding interaction. To the best of our knowledge, this work is the first to explore the role of Mg 2+ in modifying the Ca 2+ affinity of cTnC mutations linked to HCM. Our results indicate a physiologically significant role for cellular Mg 2+ both at baseline and when elevated on modifying the Ca 2+ binding properties of cTnC and the subsequent conformational changes which precede cardiac contraction.
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How this classification was reachedexpand
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 | 0.006 | 0.003 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.001 | 0.002 |
| Science and technology studies | 0.002 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.000 | 0.002 |
| 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 itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, 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".