Abstract
The membrane transporter anion exchanger 1 (AE1), or band 3, is a key component in the processes of carbon-dioxide transport in the blood and urinary acidification in the renal collecting duct. In both erythrocytes and the basolateral membrane of the collecting-duct α-intercalated cells, the role of AE1 is to catalyze a one-for-one exchange of chloride for bicarbonate. After decades of biochemical and functional studies, the structure of the transmembrane region of AE1, which catalyzes the anion-exchange reaction, has finally been determined. Each protomer of the AE1 dimer comprises two repeats with inverted transmembrane topologies, but the structures of these repeats differ. This asymmetry causes the putative substrate-binding site to be exposed only to the extracellular space, consistent with the expectation that anion exchange occurs via an alternating-access mechanism. Here, we hypothesize that the unknown, inward-facing conformation results from inversion of this asymmetry, and we propose a model of this state constructed using repeat-swap homology modeling. By comparing this inward-facing model with the outward-facing experimental structure, we predict that the mechanism of AE1 involves an elevator-like motion of the substrate-binding domain relative to the nearly stationary dimerization domain and to the membrane plane. This hypothesis is in qualitative agreement with a wide range of biochemical and functional data, which we review in detail, and suggests new avenues of experimentation.
Highlights
The major integral membrane protein of the human erythrocyte, known as band 3 or anion exchanger 1 (AE1), catalyzes the electroneutral exchange of Cl− and HCO3− across the plasma membrane, which is one of the key steps in CO2 transport in the blood (Wieth et al, 1982; Passow, 1986)
AE1 is a member of the SLC4 family of transporters, which includes Cl−/HCO3− exchangers as well as electrogenic and electroneutral Na+/HCO3− symporters (Romero et al, 2013)
The OF and IF structures serve as a framework to interpret the large body of published biochemical, genetic, and transport data, which we review briefly, and suggest new experiments to further evaluate the mechanism of AE1
Summary
The major integral membrane protein of the human erythrocyte, known as band 3 or anion exchanger 1 (AE1), catalyzes the electroneutral exchange of Cl− and HCO3− across the plasma membrane, which is one of the key steps in CO2 transport in the blood (Wieth et al, 1982; Passow, 1986). This structural difference is crucial, as it is the reason why the putative anion-binding site is exposed to the extracellular space It follows from this analysis that a hypothetical model in which repeat A is assumed to adopt the conformation of repeat B, and vice versa, ought to be an IF state. This “repeat-swapping” modeling strategy has reliably predicted the global conformational changes of transporters with widely varying structural folds, revealing both rocking-like motions (Forrest et al, 2008; Radestock and Forrest, 2011) and elevator-like motions (Crisman et al, 2009; Vergara-Jaque et al, 2015; Mulligan et al, 2016) We followed this approach to predict the unknown structure of the IF state of the AE1 membrane domain. The OF and IF structures serve as a framework to interpret the large body of published biochemical, genetic, and transport data, which we review briefly, and suggest new experiments to further evaluate the mechanism of AE1
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