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Lookup NU author(s): Dr Noel Edwards, Dr Catriona AndersonORCiD, Nichola Conlon, Andrew Watson, Dr Tim Cheek, Emeritus Professor T. Martin Embley FMedSci FRSORCiD, Professor David Thwaites
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2017 The Author(s) Amino acid transporters are essential components of prokaryote and eukaryote cells, possess distinct physiological functions, and differ markedly in substrate specificity. Amino acid transporters can be both drug targets and drug transporters (bioavailability, targeting) with many monogenic disorders resulting from dysfunctional membrane transport. The largest collection of amino acid transporters (including the mammalian SLC6, SLC7, SLC32, SLC36, and SLC38 families), across all kingdoms of life, is within the Amino acid-Polyamine-organoCation (APC) superfamily. The LeuT-fold is a paradigm structure for APC superfamily amino acid transporters and carriers of sugars, neurotransmitters, electrolytes, osmolytes, vitamins, micronutrients, signalling molecules, and organic and fatty acids. Each transporter is specific for a unique sub-set of solutes, specificity being determined by how well a substrate fits into each binding pocket. However, the molecular basis of substrate selectivity remains, by and large, elusive. Using an integrated computational and experimental approach, we demonstrate that a single position within the LeuT-fold can play a crucial role in determining substrate specificity in mammalian and arthropod amino acid transporters within the APC superfamily. Systematic mutation of the amino acid residue occupying the equivalent position to LeuT V104 titrates binding pocket space resulting in dramatic changes in substrate selectivity in exemplar APC amino acid transporters including PAT2 (SLC36A2) and SNAT5 (SLC38A5). Our work demonstrates how a single residue/site within an archetypal structural motif can alter substrate affinity and selectivity within this important superfamily of diverse membrane transporters.
Author(s): Edwards N, Anderson CMH, Conlon NJ, Watson AK, Hall RJ, Cheek TR, Embley TM, Thwaites DT
Publication type: Article
Publication status: Published
Journal: Cellular and Molecular Life Sciences
Year: 2018
Volume: 75
Issue: 5
Pages: 921-938
Print publication date: 01/03/2018
Online publication date: 23/10/2017
Acceptance date: 02/10/2017
Date deposited: 02/11/2017
ISSN (print): 1420-682X
ISSN (electronic): 1420-9071
Publisher: Birkhauser Verlag AG
URL: https://doi.org/10.1007/s00018-017-2677-8
DOI: 10.1007/s00018-017-2677-8
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