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

DOI: 10.15252/embj.2020105164 DOI Help

Authors: Dorota Focht (Aarhus University) , Caroline Neumann (Aarhus University) , Joseph Lyons (Aarhus University) , Ander Eguskiza Bilbao (Aarhus University) , Rickard Blunck (Université de Montréal) , Lina Malinauskaite (MRC Laboratory of Molecular Biology) , Ilona O Schwarz (Columbia University Vagelos College of Physicians and Surgeons) , Jonathan A Javitch (Columbia University Vagelos College of Physicians and Surgeons; New York State Psychiatric Institute) , Matthias Quick (Columbia University Vagelos College of Physicians and Surgeons; New York State Psychiatric Institute) , Poul Nissen (Aarhus University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: The Embo Journal , VOL 40

State: Published (Approved)
Published: January 2021

Abstract: 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.

Subject Areas: Biology and Bio-materials, Chemistry

Instruments: I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Other Facilities: PXI at Swiss Light Source

Added On: 01/02/2021 14:16

Discipline Tags:

Biochemistry Chemistry Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)