Insights Into the Na <sup>+</sup> ‐Dependent Anion Exchange in the SLC4 Family From the Cryo‐EM Structure of the Sodium‐Driven Chloride/Bicarbonate Exchanger SLC4A8
Bibliographic record
Abstract
SLC4 transporters are involved in the transport of HCO 3 ‾, CO 3 2 ‾, Na + , Cl‾ and H + required for regulation of pH and ion homeostasis in several important physiological processes. Dysfunction of these transporters can lead to acid‐base abnormalities, pH dysregulation, and various disease processes. Understanding of their transport mechanism is therefore critical for development of pharmacological strategies for SLC4‐related diseases. The studies of the SLC4 transport mechanisms have been hindered by lack of information on the specific substrate binding sites within the protein matrix. No binding sites have been resolved in the two previously published structures of SLC4 proteins, the chloride/bicarbonate anion exchanger 1 (AE1, SLC4A1) and the electrogenic sodium carbonate cotransporter 1 (NBCe1, SLC4A4), although putative binding sites have been identified on the basis of these structures from computational modelling and functional mutagenesis experiments. Here we present a new cryo‐EM structure at 3.4Å of the outward facing open (OF) conformation of the sodium dependent chloride/bicarbonate exchanger (NDCBE, SLC4A8) [1], which exchanges Na + ‐CO 3 2 ‾ for Cl‾, combining the feature functionalities of both AE1 and NBCe1. The structure resolves for the first time a Na + and a CO 3 2 ‾ ion bound at the center of the protein in the area of the previously identified putative binding site S1 in NBCe1 and AE1. Mutation of the residues involved in ion binding leads to significant impairment of NDCBE transport. Computational modelling with the new NDCBE structure outlines two separate ion pathways for cations and anions in the OF cavity and demonstrates that a Na + ion bound at D800 is necessary for anion binding in site S1 and that a Na + ‐CO 3 2 ‾ ion pair in this site is the most likely ion load. A second anion binding site, S2, is also identified in the permeation cavity in proximity to site S1. We conclude that Na + ‐dependent transport in the SLC4 family is influenced both by thermodynamic effects at the S1 binding site and by permeation effects governed by the residues lining the cation and anion permeation pathways in the OF cavity and site S2. [1] Wang W, Tsirulnikov K, Zhekova HR, et al. Cryo‐EM structure of the sodium‐driven chloride/bicarbonate exchanger NDCBE. Nat Commun. 2020;12: 5690
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.002 | 0.000 |
| Research integrity | 0.000 | 0.002 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".