Organization and Dynamics of the Red Blood Cell Band 3 Anion Exchanger SLC4A1: Insights From Molecular Dynamics Simulations.

Antreas C Kalli,Reinhart A F Reithmeier

doi:10.3389/fphys.2022.817945

Antreas C Kalli, Reinhart A F Reithmeier

Open Access

https://doi.org/10.3389/fphys.2022.817945

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Abstract

Molecular dynamics (MD) simulations have provided new insights into the organization and dynamics of the red blood cell Band 3 anion exchanger (AE1, SLC4A1). Band 3, like many solute carriers, works by an alternating access mode of transport where the protein rapidly (104/s) changes its conformation between outward and inward-facing states via a transient occluded anion-bound intermediate. While structural studies of membrane proteins usually reveal valuable structural information, these studies provide a static view often in the presence of detergents. Membrane transporters are embedded in a lipid bilayer and associated lipids play a role in their folding and function. In this review, we highlight MD simulations of Band 3 in realistic lipid bilayers that revealed specific lipid and protein interactions and were used to re-create a model of the Wright (Wr) blood group antigen complex of Band 3 and Glycophorin A. Current MD studies of Band 3 and related transporters are focused on describing the trajectory of substrate binding and translocation in real time. A structure of the intact Band 3 protein has yet to be achieved experimentally, but cryo-electron microscopy in combination with MD simulations holds promise to capture the conformational changes associated with anion transport in exquisite molecular detail.

Highlights

Band 3, the red blood cell Cl−/HCO3− anion exchanger 1 (AE1), is the founding member of the SLC4 family of bicarbonate transporters and plays an essential role in respiration (Alper, 2009; Cordat and Reithmeier, 2014; Jennings, 2021)
These dynamic insights will reveal how Band 3 works at the molecular level and how mutations associated with disease affect their ability to fold and function properly
Fatty acylated residues are typically located at the membrane interface with the fatty acid positioned along with other fatty acyl groups in the lipid bilayer (Cheung and Reithmeier, 2004). This indicates that TM13 has a dynamic aspect and that the non-enzymatic palmitoylation of Cys843 may occur as red blood cells age and be part of the senescence clock

Summary

INTRODUCTION

Band 3, the red blood cell Cl−/HCO3− anion exchanger 1 (AE1), is the founding member of the SLC4 family of bicarbonate transporters and plays an essential role in respiration (Alper, 2009; Cordat and Reithmeier, 2014; Jennings, 2021). The crystal structure of the dimeric membrane domain in the outward-facing conformation (Arakawa et al, 2015; Reithmeier et al, 2016; Figure 2) reveals a complex folding pattern with 14 transmembrane (TM) segments in a 7 + 7 TM inverted repeat common to members of the SLC4 family, the related SLC26 anion transporter family, and the unrelated SLC23 family of nucleobase transporters (Chang and Geertsma, 2017). MD simulations are ideally suited to explore these issues since this powerful computational method provides a direct link between the structure and the conformational landscape accessible to the protein molecule These dynamic insights will reveal how Band 3 works at the molecular level and how mutations associated with disease affect their ability to fold and function properly. Band 3 subunits work independently (Macara and Cantley, 1981)

MOLECULAR DYNAMICS SIMULATIONS

Molecular dynamics simulations and modeling of intact Band

ROCKER AND ELEVATOR TRANSPORT MODELS

CONCLUSION