@article {30797,
	title = {Transmembrane helices 5 and 12 control transport dynamics, substrate affinity, and specificity in the elevator-type UapA transporter.},
	journal = {Genetics},
	volume = {222},
	year = {2022},
	month = {2022 Aug 30},
	abstract = {An increasing number of solute transporters have been shown to function with the so-called sliding-elevator mechanism. 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. One of the best-studied elevator transporters is the UapA uric acid-xanthine/H+ symporter of the filamentous fungus Aspergillus nidulans. Here, we present a genetic analysis for deciphering the role of transmembrane segments (TMS) 5 and 12 in UapA transport function. We show that specific residues in both TMS5 and TMS12 control, negatively or positively, the dynamics of transport, but also substrate binding affinity and specificity. More specifically, mutations in TMS5 can lead not only 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. Our findings shed new light on how elevator transporters function and how this knowledge can be applied to genetically modify their transport characteristics.},
	keywords = {Aspergillus nidulans, Biological Transport, Fungal Proteins, Membrane Transport Proteins, Substrate Specificity},
	issn = {1943-2631},
	doi = {10.1093/genetics/iyac107},
	author = {Dimakis, Dimitris and Pyrris, Yiannis and Diallinas, George}
}
