Molecular insights into the structural and dynamical changes of calcium channel TRPV6 induced by its interaction with phosphatidylinositol 4,5-bisphosphate
Bibliographic record
Abstract
Transient receptor potential vanilloid subfamily member 6 (TRPV6) is an epithelial Ca 2+ channel that regulates the initial step of the transcellular Ca 2+ transport pathway. TRPV6 is expressed in the kidney, intestine, placenta, and other tissues, and the dysregulation of the channel is implicated in several human cancers. It has been reported that phosphatidylinositol 4,5-bisphosphate (PIP 2 ) activates TRPV6 and its close homologue TRPV5; however, the underlying molecular mechanism is less clear. Recently, a structure of rabbit TRPV5 in complex with dioctanoyl (diC 8 ) PIP 2 , a soluble form of PIP 2 , was determined by cryo-electron microscopy. Based on this structure, the structural model of human TRPV6 with PIP 2 was set up, and then molecular dynamics simulations were performed for TRPV6 with and without PIP 2 . Simulation results show that the positively charged residues responsible for TRPV5 binding of diC 8 PIP 2 are involved in the interactions between TRPV6 and PIP 2 . The binding of PIP 2 to TRPV6 increases the distance between the diagonally opposed residues D542 in the selectivity filter and that between the diagonally opposed M578 residues in the lower gate of TRPV6. A secondary structural analysis reveals that residues of M578 in TRPV6 undergo structural and position changes during binding of PIP 2 with TRPV6. In addition, principal component analysis indicates that the binding of PIP 2 increases the dynamical motions of both the selectivity filter and the lower gate of TRPV6. These changes induced by PIP 2 favor the channel opening. Thus, this study provides a basis for understanding the mechanism underlying the PIP 2 -induced TRPV6 channel activation.
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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".