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Cellular and Molecular Life Sciences

, Volume 74, Issue 12, pp 2299–2318 | Cite as

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

  • Jonas Protze
  • Doreen Braun
  • Katrin Manuela Hinz
  • Dorothea Bayer-Kusch
  • Ulrich Schweizer
  • Gerd Krause
Original Article

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.

Keywords

MFS-transporter Thyroid hormones Membrane proteins Structure–function study Mutagenesis Molecular modelling 

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

Notes

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).

Supplementary material

18_2017_2461_MOESM1_ESM.pdf (876 kb)
Supplementary material 1 (PDF 876 KB)
18_2017_2461_MOESM2_ESM.pdf (499 kb)
Supplementary material 2 (PDF 499 KB)
18_2017_2461_MOESM3_ESM.wmv (20.6 mb)
Supplementary material 3 (WMV 21103 KB)

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Copyright information

© Springer International Publishing 2017

Authors and Affiliations

  1. 1.Leibniz-Institut für Molekulare Pharmakologie (FMP)BerlinGermany
  2. 2.Institut für Biochemie und MolekularbiologieRheinische Friedrich-Wilhelms-UniversitätBonnGermany

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