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Membrane-traversing mechanism of thyroid hormone transport by monocarboxylate transporter 8

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Abstract

Monocarboxylate transporter 8 (MCT8) mediates thyroid hormone (TH) transport across the plasma membrane in many cell types. In order to better understand its mechanism, we have generated three new MCT8 homology models based on sugar transporters XylE in the intracellular opened (PDB ID: 4aj4) and the extracellular partly occluded (PDB ID: 4gby) conformations as well as FucP (PDB ID: 3o7q) and GLUT3 (PDB ID: 4zwc) in the fully extracellular opened conformation. T3-docking studies from both sides revealed interactions with His192, His415, Arg445 and Asp498 as previously identified. Selected mutations revealed further transport-sensitive positions mainly at the discontinuous transmembrane helices TMH7 and 10. Lys418 is potentially involved in neutralising the charge of the TH substrate because it can be replaced by charged, but not by uncharged, amino acids. The side chain of Thr503 was hypothesised to stabilise a helix break at TMH10 that undergoes a prominent local shift during the transport cycle. A T503V mutation accordingly affected transport. The aromatic Tyr419, the polar Ser313 and Ser314 as well as the charged Glu422 and Glu423 lining the transport channel have been studied. Based on related sugar transporters, we suggest an alternating access mechanism for MCT8 involving a series of amino acid positions previously and newly identified as critical for transport.

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Abbreviations

AHDS:

Allan–Herndon–Dudley syndrome

FucP:

E. coli fucose/H+ symporter

GlpT:

Glycerol-3-phosphate transporter

GLUT3:

Glucose transporter 3

T3 :

3,3′,5-Triiodothyronie

T4 :

3,3′,5,5′-Tetraiodothyronine

TH:

Thyroid hormone

TM:

Transmembrane

TMH:

Transmembrane helix

XylE:

E. coli d-xylose:H+ symporter

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Acknowledgements

The authors thank Simone Arndt and Tobias Lindenberg for excellent technical assistance, Catherine L. Worth for critically reading the paper before submission and acknowledge funding by Deutsche Forschungsgemeinschaft DFG THYROID TRANS ACT KR1273/5-1 (GK), Schw914/3-1 (US) and the Sherman family (US).

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    Authors and Affiliations

    1. Leibniz-Institut für Molekulare Pharmakologie (FMP), Robert-Rössle-Str. 10, 13125, Berlin, Germany

      Jonas Protze, Katrin Manuela Hinz & Gerd Krause

    2. Institut für Biochemie und Molekularbiologie, Rheinische Friedrich-Wilhelms-Universität, 53115, Bonn, Germany

      Doreen Braun, Dorothea Bayer-Kusch & Ulrich Schweizer

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    1. Jonas Protze
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    2. Doreen Braun
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    Correspondence to Ulrich Schweizer or Gerd Krause.

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    J. Protze and D. Braun, as well as U. Schweizer and G. Krause contributed equally to this work.

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    Protze, J., Braun, D., Hinz, K.M. et al. Membrane-traversing mechanism of thyroid hormone transport by monocarboxylate transporter 8. Cell. Mol. Life Sci. 74, 2299–2318 (2017). https://doi.org/10.1007/s00018-017-2461-9

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