Transport Mechanism Insights from Newly Identified Substrate Binding Sites in Two SLC4 Transporters
Bibliographic record
Abstract
The secondary transporters from the SLC4 family are involved in transmembrane transport of HCO 3 − , CO 3 2 − , Na + , Cl − and H + ions necessary for pH maintenance, blood pressure, and ion homeostasis in the organism. Two outward facing structures of members of the SLC4 family, the human anion exchanger 1 (SLC4A1, hAE1) and the human electrogenic sodium bicarbonate cotransporter 1 (SLC4A4, hNBCe1) have been resolved previously with X‐Ray and Cryo‐EM spectroscopy and reveal a common 3D fold with a large ion and water permeation cavity, lined with basic and acidic residues. The exact position and composition of the binding sites within the cavity are as of yet unknown, since the available structures did not resolve bound ions. Several residues of transport significance have been identified from previous functional mutagenesis studies. Here we make use of multiple molecular dynamics simulations and functional mutagenesis measurements to identify putative binding sites in hAE1 and hNBCe1. We hypothesize that the surprisingly different transport modes of hAE1 and hNBCe1 (exchanger vs symporter, respectively) are governed by a small number of residues in the ion binding pocket. Our computational and experimental results provide evidence for the existence of two binding sites (entry and central) in the outward facing cavity of hAE1 and hNBCe1. The newly identified binding sites feature charged, polar and hydrophobic residues with potential specific roles in ion selectivity, pH sensing, substrate coordination, and gating and provide basis for distinction between the transport modes of hAE1 and hNBCe1.
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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) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| 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".