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A non-helical region in transmembrane helix 6 of hydrophobic amino acid transporter MhsT mediates substrate recognition

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  • Dorota Focht
  • ,
  • Caroline Neumann
  • Joseph Lyons
  • Ander Eguskiza Bilbao
  • ,
  • Rickard Blunck, Universite de Montreal
  • ,
  • Lina Malinauskaite
  • ,
  • Ilona O. Schwarz, Columbia University
  • ,
  • Jonathan A. Javitch, Columbia University, New York State Psychiatric Institute
  • ,
  • Matthias Quick, Columbia University, New York State Psychiatric Institute
  • ,
  • Poul Nissen

MhsT of Bacillus halodurans is a transporter of hydrophobic amino acids and a homologue of the eukaryotic SLC6 family of Na+-dependent symporters for amino acids, neurotransmitters, osmolytes, or creatine. The broad range of transported amino acids by MhsT prompted the investigation of the substrate recognition mechanism. Here, we report six new substrate-bound structures of MhsT, which, in conjunction with functional studies, reveal how the flexibility of a Gly-Met-Gly (GMG) motif in the unwound region of transmembrane segment 6 (TM6) is central for the recognition of substrates of different size by tailoring the binding site shape and volume. MhsT mutants, harboring substitutions within the unwound GMG loop and substrate binding pocket that mimick the binding sites of eukaryotic SLC6A18/B0AT3 and SLC6A19/B0AT1 transporters of neutral amino acids, exhibited impaired transport of aromatic amino acids that require a large binding site volume. Conservation of a general (G/A/C)ΦG motif among eukaryotic members of SLC6 family suggests a role for this loop in a common mechanism for substrate recognition and translocation by SLC6 transporters of broad substrate specificity.

TidsskriftEMBO Journal
Antal sider13
StatusUdgivet - jan. 2021

Bibliografisk note

Funding Information:
The authors are grateful to technical assistance by Tetyana Klymchuk, Lotte T. Pedersen, Anna Marie Nielsen, and Audrey Warren and support for computing by Jesper L. Karlsen. We thank Steffen Sinning and Birgit Schiøtt for fruitful discussions. Work on the project was supported by a Short Term EMBO Fellowship [ASTF 80‐2016] and Boehringer Ingelheim Fonds travel grant (2015) to DF, a PhD fellowship from the Lundbeck Foundation to CN (2015‐3225), a PhD fellowship from the Boehringer Ingelheim Fonds to LM (2010), and a post‐doctoral fellowship from the Lundbeck Foundation to JAL (2015‐2704). The research was supported by NIH grants U54GM087519 and R01DA04510 to JAJ, R01GM119396 to MQ, and by the Lundbeck Foundation grants 2011‐3868 and 2016‐2518 to PN.

Publisher Copyright:
© 2020 The Authors

Copyright 2021 Elsevier B.V., All rights reserved.

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