High affinity uric acid-xanthine permease, UapA. Functionaly critical residues in transmembrane segments 1 and 3 have been identified (Amillis et al., 2011). The substrate recognition and transport pathway have been proposed (Kosti et al., 2012; Kosti et al. 2010).  UapA oligomerization is essential for membrane trafficking and turnover and is a common theme in fungi and mammalian cells (Martzoukou et al. 2015).  Specificity is determined by the interactions of a given substrate with the TMS8-9 loop and by interactions of this loop with TMS1 and TMS12 (Papageorgiou et al. 2008). F528 and Q408 in TMS 12 are important for substrate recognition, and mutation of the former results in high efficiency uptake of several purines and pyrimidines not otherwise transported (Vlanti et al. 2006). A high resolution structure of UapA is available, and it is formed from two domains, a core domain and a gate domain, similar to the previously solved uracil transporter UraA, which belongs to the same family (Alguel et al. 2016). The structure shows UapA in an inward-facing conformation with xanthine bound to residues in the core domain. Unlike UraA, which is a monomer, UapA forms a dimer in the crystals with dimer interactions formed exclusively through the gate domain. Analysis of dominant negative mutants is consistent with dimerization playing a key role in transport. Alguel et al. 2016 postulated that UapA uses an elevator transport mechanism likely to be shared with other structurally homologous transporters including anion exchangers and prestin. Specific residues in UapA are critical for dimerization, ER-exit and function (Kourkoulou et al. 2019). Despite structural and functional differences, all elevator-type transporters use a common mechanism of substrate translocation via reversible movements of a mobile core domain (the elevator) hosting the substrate binding site along a rigid scaffold domain stably anchored in the plasma membrane via homodimerization (Dimakis et al. 2022). One of the best studied elevator transporters is the UapA uric acid-xanthine/H+ symporter of the filamentous fungus Aspergillus nidulans. TMSs 5 and 12 in UapA control, negatively or positively, the dynamics of transport as well as substrate binding affinity and specificity. Mutations in TMS5 can lead to increased rate of transport, but also to an inactive transporter due to high-affinity substrate-trapping, whereas mutations in TMS12 lead to apparently uncontrolled sliding and broadened specificity, leading in specific cases to UapA-mediated purine toxicity.  The interactome of the UapA transporter revealed putative new players in anterograde membrane cargo trafficking(Georgiou et al. 2023). High-resolution structures of UapA revealed aspects of the elevator-type transport mechanism (Broutzakis et al. 2024).  Full-length cryo-EM structures of UapA in the inward-facing apo- and substrate-loaded conformations at 2.05-3.5 Å in detergent and lipid nanodiscs were determined.  The role of water molecules and lipids in substrate binding, specificity, dimerization, and activity were revealed as were  the elevator-type transport mechanism and the evolution of extended cytosolic tails in eukaryotic transporters, apparently needed for subcellular trafficking (Broutzakis et al. 2024),