The effect of magnesium on calcium binding to cardiac troponin C related hypertrophic cardiomyopathy mutants
Bibliographic record
Abstract
Abstract Cardiac troponin C (cTnC) is the calcium (Ca 2+ ) sensing component of the troponin complex. Binding of Ca 2+ to cTnC triggers a cascade of myofilament conformational changes that culminate in force production. Mutations in cTnC linked to hypertrophic myocardial myopathy (HCM) induce a a greater degree and duration of Ca 2+ binding, which may underly the hypertrophic phenotype. Recent evidence from our laboratories demonstrated novel modifications of cTnC Ca 2+ binding by cellular magnesium (Mg 2+ ) that we hypothesize may be of significance in promoting HCM. Regulation of contraction has long been thought to occur exclusively through Ca 2+ binding to site II of cTnC. However, abundant cellular Mg 2+ is a potential competitor for binding to the same sites; work by several groups also suggests this is possible. We have used isothermal titration calorimetry (ITC) to explore the thermodynamic properties associated with the interaction between Ca 2+ /Mg 2+ and site II of cTnC; these experiments demonstrated that physiological concentrations of Mg 2+ may compete with Ca 2+ to bind site II of cTnC. In experiments reported here, we studied a series of mutations in cTnC thought to be causal in HCM. Three mutants (A8V, L29Q, and A31S) slightly elevated the affinity for both Ca 2+ and Mg 2+ , whereas other mutants (L48Q, Q50R, and C84Y), that are closer to the C-terminal domain and surrounding the EF hand binding motif of site II had 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 ofcTnC mutations linked to HCM. Our results indicate a physiologically significant role for cellular Mg 2+ at baseline conditions and when elevated on the control of the dynamics of contraction by modifications in the Ca 2+ binding properties of cTnC.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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) | 0.001 | 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 | 0.001 | 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".