Molecular Insights into the Structural and Dynamical Changes of Calcium Channel TRPV6 Induced by Its Interaction with Phosphatidylinositol 4,5-Bisphosphate
Bibliographic record
Abstract
Background: Transient receptor potential vanilloid subfamily member 6 (TRPV6) is a Ca2+-selective channel that mediates Ca2+ entry into epithelial cells as the first step of the transcellular Ca2+ transport pathway. TRPV6 is expressed in the kidney, intestine, and other epithelial tissues, and the dysregulation of this channel has been implicated in cancers. TRPV6 and its close homologue TRPV5 are activated by phosphatidylinositol 4,5-bisphosphate (PIP2); however, it is less clear how PIP2 activates TRPV6 at the molecular level. Methods: Recently, a structure of rabbit TRPV5 in complex with dioctanoyl (diC8) PIP2, a soluble form of PIP2, was determined by cryo-electron microscopy. Based on this structure, a structural model of human TRPV6 with PIP2 was set up. This model was then embedded in a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) lipid bilayer with water molecules added on both sides of the bilayer using CHARMM-GUI. Using the AMBER18 software, three 500-ns molecular dynamics simulations were performed for the two systems of TRPV6 with and without PIP2. Results: Interaction energy analyses show that the positively charged residues K300, R302, R305, K484, and R584 of TRPV6 play important roles in the binding of PIP2, which is consistent with the structural data that residues R302 and K484 in TRPV5 are responsible for the binding of diC8 PIP2. The binding of PIP2 to TRPV6 increases the distance between the diagonally opposed residues D542 in the selectivity filter as well as the distance between the diagonally opposed residues M578 in the lower gate. Secondary structure and density analyses show that residue M578 in TRPV6 in the presence of PIP2 undergoes structural and position changes, suggesting the opening of the lower gate. Principal component analysis also indicates that the binding of PIP2 increases the dynamic motion of both the selectivity filter and the lower gate of TRPV6. Conclusions: Simulation results indicate that PIP2 increases the fluctuation of the key residues in both the selectivity filter and the lower gate of TRPV6. In addition, PIP2 reduces the helix occupancy of a key residue in the lower gate. Furthermore, the diameters of both the selectivity filter and the lower gate are increased by PIP2. These changes likely contribute to the opening of the TRPV6 channel. Funding: NIDDK Support
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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 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".