A three-way inter-molecular network accounts for the CaVα2δ1-induced functional modulation of the pore-forming CaV1.2 subunit
Bibliographic record
Abstract
L-type Ca V 1.2 channels are essential for the excitation–contraction coupling in cardiomyocytes and are hetero-oligomers of a pore-forming Ca V α1C assembled with Ca V β and Ca V α2δ1 subunits. A direct interaction between Ca V α2δ1 and Asp-181 in the first extracellular loop of Ca V α1 reproduces the native properties of the channel. A 3D model of the von Willebrand factor type A (VWA) domain of Ca V α2δ1 complexed with the voltage sensor domain of Ca V α1C suggests that Ser-261 and Ser-263 residues in the metal ion–dependent adhesion site (MIDAS) motif are determinant in this interaction, but this hypothesis is untested. Here, coimmunoprecipitation assays and patch-clamp experiments of single-substitution variants revealed that Ca V α2δ1 Asp-259 and Ser-261 are the two most important residues in regard to protein interactions and modulation of Ca V 1.2 currents. In contrast, mutating the side chains of Ca V α2δ1 Ser-263, Thr-331, and Asp-363 with alanine did not completely prevent channel function. Molecular dynamics simulations indicated that the carboxylate side chain of Ca V α2δ1 Asp-259 coordinates the divalent cation that is further stabilized by the oxygen atoms from the hydroxyl side chain of Ca V α2δ1 Ser-261 and the carboxylate group of Ca V α1C Asp-181. In return, the hydrogen atoms contributed by the side chain of Ser-261 and the main chain of Ser-263 bonded the oxygen atoms of Ca V 1.2 Asp-181. We propose that Ca V α2δ1 Asp-259 promotes Ca 2+ binding necessary to produce the conformation of the VWA domain that locks Ca V α2δ1 Ser-261 and Ser-263 within atomic distance of Ca V α1C Asp-181. This three-way network appears to account for the Ca V α2δ1-induced modulation of Ca V 1.2 currents.
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) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 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".