Comparison of a repeat-swap model of AE1 with the OF H2DIDS-bound x-ray crystal structure predicts an elevator-like conformational change, where the transporter domain (cyan and yellow) rotates and moves inwards, relative to the scaffold domain (red and blue). (A–D) Individual protomers are viewed and helices are colored according to Fig. 1. The structures are viewed from the extracellular side (A and C), the plane of the membrane, highlighting the inward movement of the transport domain and the putative substrate-binding site encompassed therein (B), or the cytoplasmic side (D). The protein is shown as cartoon helices (A and B) or surface (C), with H2DIDS and residues K539, E535, and K851, which line the pathway in the OF structure, shown as sticks. The E681 side chain, which is thought to be at the substrate binding site, is shown as spheres. This extracellular pathway is closed in the repeat-swapped model (C). In contrast, a new pathway opens up from the cytoplasmic side (D) that leads to residues assumed to form the anion-binding site (white). The model predicts a two-domain motion, where the teal and orange helices are displaced by ∼11 Å and rotated by ∼17°. This movement requires the linker helices H2 and H3 (gray cartoon helices) to change their tilt angle relative to the membrane surface.
