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ORIGINAL RESEARCH article

Front. Physiol.
Sec. Membrane Physiology and Membrane Biophysics
Volume 15 - 2024 | doi: 10.3389/fphys.2024.1474628
This article is part of the Research Topic Advances in Acid-Base Physiology: From Single Transporters to Physiology View all 6 articles

On the Substrate Turnover Rate of NBCe1 and AE1 SLC4 Transporters: Structure-Function Considerations

Provisionally accepted
Alexander Pushkin Alexander Pushkin 1Liyo Kao Liyo Kao 1Hristina R Zhekova Hristina R Zhekova 2Rustam Azimov Rustam Azimov 1Natalia Abuladze Natalia Abuladze 1Xuesi Max Shao Xuesi Max Shao 1D Peter Tieleman D Peter Tieleman 2Ira Kurtz Ira Kurtz 1*
  • 1 University of California, Los Angeles, Los Angeles, United States
  • 2 University of Calgary, Calgary, Alberta, Canada

The final, formatted version of the article will be published soon.

    A transport protein's turnover rate (TOR) is the maximum rate of substrate translocation under saturating conditions. This parameter represents the number of transporting events per transporter molecule (assuming a single transport site) per second (s). From this standpoint, a transporter's TOR is similar to an enzyme's catalytic constant. Knowledge of a transporter's TOR allows comparison of the transport capacity of various transporters at the molecular level as well as the total transport per cell and whole organ levels. Despite this, there is currently a very limited number of transporters, for which TOR has been determined experimentally. In the SLC4 transporter family of CO3 2 ‾/HCO3‾ transporters, erythrocyte AE1 (eAE1; SLC4A1) is the only member, for which TOR has been determined (~50,000 s -1 ). Whether other SLC4 family members have similar TOR values is currently unknown. Here we report TOR measurements of the electrogenic Na + -CO3 2 ‾ cotransporter NBCe1-A (SLC4A4) and the kidney specific AE1 splice variant, kAE1, that play important roles in renal bicarbonate absorption and are mutated in proximal and distal renal tubular acidosis respectively. We have also remeasured the eAE1 TOR value for comparison. NBCe1-A had a TOR value of ~15,200 s -1 whereas kAE1 and eAE1 had significantly higher values (62,000 s -1 and 60,500 s -1 respectively). We modeled the inward-facing (IF) conformation of NBCe1-A to determine conformational changes during its transport cycle.Comparison of this IF model with our previously determined cryoelectron microscopy (cryoEM) outward-facing (OF) conformation structure, demonstrates that NBCe1-A has an elevator-type transport mechanism with a small vertical ~5 Å shift of the ion coordination site as we have previously shown for AE1. We speculate that this very small vertical movement plays an important role in contributing to the very high TOR numbers of SLC4 transporters.

    Keywords: ion turnover rate, bicarbonate, Carbonate, transport, renal tubular acidosis, NBCe1-A, AE1

    Received: 01 Aug 2024; Accepted: 25 Nov 2024.

    Copyright: © 2024 Pushkin, Kao, Zhekova, Azimov, Abuladze, Shao, Peter Tieleman and Kurtz. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Ira Kurtz, University of California, Los Angeles, Los Angeles, United States

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