FurE, a member of the NCS1 transporter family in Aspergillus nidulans, is specific for allantoin, uric acid, uracil and related analogues. Herein, we show that C- or N-terminally truncated FurE transporters (FurE-ΔC or FurE-ΔΝ) present increased protein stability, but also inability for uric acid transport. To better understand the role of cytoplasmic terminal regions, we characterized genetic suppressors that restore FurE-ΔC-mediated uric acid transport. Suppressors map in the periphery of the substrate-binding site (Thr133 in TMS3 and Val343 in TMS8), an outward-facing gate (Ser296 in TMS7, Ile371 in TMS9, Tyr392 and Leu394 in TMS10) or in flexible loops (Asp26 in LN, Gly222 in L5, Asn308 in L7). Selected suppressors were shown to also restore the wild-type specificity of FurE-ΔΝ, suggesting that both C- and/or N-terminal domains are involved in intramolecular dynamics critical for substrate selection. A direct, substrate-sensitive, interaction of C- and/or N-terminal domains was supported by bimolecular fluorescence complementation assays. To our knowledge, this is the first case where not only the function, but also, the specificity of a eukaryotic transporter is regulated by its terminal cytoplasmic regions.