Fig. 6: A scheme of the transport cycle and structural differences in concentrators and exchangers from the SLC1A family.

The upper part depicts outward-facing protomers displaying the structural rearrangements of HP2 and TM7 at various stages of the transport cycle, with the respective schematic representation of protomers below. Considering the reversible nature of secondary transporters and the structural equivalence of the binding sites in the outward- and inward-facing states, the structural transitions apply to both outward- and inward-facing conformations. The transport and scaffold domains are visualized in blue and yellow, respectively, with displayed HP2 gate (closed in salmon and open in purple) and TM7 (compact in dark yellow and extended in orange). The membrane boundaries are shown as gray shadows. The part of the transport cycle restricted in exchangers is indicated by a red box, and crossed arrows signal the transition to the conformation that exchangers do not sample. In contrast to concentrators, upon substrate release, ASCT2 retains a bound Na⁺ ion with a rigid TM7 in a compact state, prohibiting closure of the HP2 gate and a reorientation to the apo state, thereby effectively confining ASCT2 to an exchange mode.