Size does matter: 18 amino acids at the N-terminal tip of an amino acid transporter in Leishmania determine substrate specificity



Long N-terminal tails of amino acid transporters are known to act as sensors of the internal pool of amino acids and as positive regulators of substrate flux rate. In this study we establish that N-termini of amino acid transporters can also determine substrate specificity. We show that due to alternative trans splicing, the human pathogen Leishmania naturally expresses two variants of the proline/alanine transporter, one 18 amino acid shorter than the other. We demonstrate that the longer variant (LdAAP24) translocates both proline and alanine, whereas the shorter variant (∆18LdAAP24) translocates just proline. Remarkably, co-expressing the hydrophilic N-terminal peptide of the long variant with ∆18LdAAP24 was found to recover alanine transport. This restoration of alanine transport could be mediated by a truncated N-terminal tail, though truncations exceeding half of the tail length were no longer functional. Taken together, the data indicate that the first 18 amino acids of the negatively charged N-terminal LdAAP24 tail are required for alanine transport and may facilitate the electrostatic interactions of the entire negatively charged N-terminal tail with the positively charged internal loops in the transmembrane domain, as this mechanism has been shown to underlie regulation of substrate flux rate for other transporters.

Sci Rep. 2015 Nov 9;5:16289. doi: 10.1038/srep16289.
Schlisselberg D1, Mazarib E1, Inbar E1, Rentsch D2, Myler PJ3,4,5, Zilberstein D1.
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1Faculty of Biology, Technion-Israel Institute of Technology, Haifa 32000, Israel.
2Institute of Plant Sciences, University of Bern, Altenbergrain 21, 3013 Bern, Switzerland.
3Seattle Biomedical Research Institute, 307 Westlake Ave N, Seattle, WA 98109-5219, USA.
4Departments of Global Health &Medical Education, University of Washington, Seattle, WA 98195, USA.
5Departments of Biomedical Informatics &Medical Education, University of Washington, Seattle, WA 98195, USA.

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