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Abstract
Equilibrative nucleoside transporters (ENTs) are integral membrane proteins, which reside in plasma membranes of all eukaryotic cells and mediate thermodynamically downhill transport of nucleosides. This process is essential for nucleoside recycling, and also plays a key role in terminating adenosine-mediated cellular signaling. Furthermore, ENTs mediate the uptake of many drugs, including anticancer and antiviral nucleoside analogues. The structure and mechanism, by which ENTs catalyze trans-membrane transport of their substrates, remain unknown. To identify the core of the transporter needed for stability, activity, and for its correct trafficking to the plasma membrane, we have expressed human ENT deletion mutants in Xenopus laevis oocytes and determined their localization, transport properties and susceptibility to inhibition. We found that the carboxyl terminal trans-membrane segments are essential for correct protein folding and trafficking. In contrast, the soluble extracellular and intracellular loops appear to be dispensable, and must be involved in the fine-tuning of transport regulation.
Highlights
Equilibrative nucleoside transporters (ENTs) are integral membrane proteins, which facilitate passive diffusion of nucleosides and nucleobases across membranes [1]
The wild type (WT) human ENT1 (hENT1) and the deletion constructs were tagged with enhanced green fluorescent protein (EGFP) at their amino-termini
RNAs encoding the EGFP-hENT1 fusion constructs were co-injected with a plasma membrane marker mch-TMEM, used as a marker of plasma membrane localization
Summary
Equilibrative nucleoside transporters (ENTs) are integral membrane proteins, which facilitate passive diffusion of nucleosides and nucleobases across membranes [1]. Together with evolutionary and structurally unrelated sodium-dependent concentrative nucleoside transporters (CNTs), ENTs play key roles in nucleoside salvage for recycling in cells [2]. They regulate the physiological levels of adenosine, a major paracrine signaling molecule and neuromodulator [2,3]. The expression levels of human ENT1 (hENT1) correlate with the success of gemcitabine chemotherapy in several types of cancer [9,10].
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