Repeat-Swap Homology Modeling of the Anion Exchanger AE1 Reveals an Elevator-Like Antiport Mechanism

Abstract

Anion Exchanger 1 (AE1), or band 3, is a membrane transporter found in erythrocytes and the kidney collecting duct. As part of the process of carbon dioxide clearance from these tissues, AE1 exchanges the accumulated bicarbonate for chloride in the blood plasma. After years of extensive biochemical and functional studies, the structure of the AE1 C-terminal domain (ACTD), which is the integral membrane domain catalyzing the anion exchange, has been finally solved at a resolution of 3.5 A. The structure comprises two structural repeats of inverted transmembrane topology, organized into what has been referred as ‘core’ and ‘gate’ domains. The two repeats are, however, structurally asymmetric and the protein adopts an outward-facing conformation. Here, we gain insights into the nature of the alternating-access mechanism of this transporter, by constructing a model of the inward-facing state using the so-called repeat-swap homology modeling method. Comparison of the resulting model of the inward-facing state with the outward-facing crystal structure reveals that anion translocation takes place by way of an elevator-type mechanism in which the core domain moves vertically relative to the gate domain, which forms the dimerization interface. Taken together, the structures can account qualitatively for a wide range of biochemical and functional data, and suggest new avenues of experimentation.