art:10.1186/1756-6614-4-S1-S4.pdf 3,97MB
1000 Titel
  • Insights into molecular properties of the human monocarboxylate transporter 8 by combining functional with structural information
1000 Autor/in
  1. Kleinau, Gunnar |
  2. Schweizer, Ulrich |
  3. Kinne, Anita |
  4. Köhrle, Josef |
  5. Grüters, Annette |
  6. Krude, Heiko |
  7. Biebermann, Heike |
1000 Erscheinungsjahr 2011
1000 LeibnizOpen
1000 Publikationstyp
  1. Artikel |
1000 Online veröffentlicht
  • 2011-08-03
1000 Erschienen in
1000 Quellenangabe
  • 4(Suppl 1): S4
1000 FRL-Sammlung
1000 Copyrightjahr
  • 2011
1000 Lizenz
1000 Verlagsversion
  • |
  • |
1000 Ergänzendes Material
  • |
1000 Publikationsstatus
1000 Begutachtungsstatus
1000 Sprache der Publikation
1000 Abstract/Summary
  • BACKGROUND: The monocarboxylate transporter 8 (MCT8) is a member of the major facilitator superfamily (MFS) and transports specificly iodothyronines. MCT8 mutations are the underlying cause of a syndrome of severe X-linked psychomotor retardation known as the Allan-Herndon-Dudley syndrome. This syndrome is characterized by abnormally high T3, low/normal T4 serum levels and slightly elevated serum TSH. To date, more than 25 pathogenic mutations in hMCT8 are known and they are valuable indicators of important regions for structural and functional MCT8 properties. METHODS: We designed a structural human MCT8 model and studied reported pathogenic missense mutations with focus on the estimation of those amino acid positions which are probably sensitive for substrate transport. Furthermore, assuming similarities between determinants of T3 binding observed in the published crystal structure of the thyroid hormone receptor beta occupied by its ligand T3 and the structural MCT8 model, we explore potential T3 binding sites in the MCT8 substrate channel cavity. RESULTS: We found that all known pathogenic missense mutations are located exclusively in the transmembrane helices and to a high degree at conserved residues among the MCT family. Furthermore, mutations either of or to prolines/glycines are located mainly at helices 9-12 and are expected to cause steric clashes or structural misfolding. In contrast, several other mutations are close to the potential substrate channel and affected amino acids are likely involved in the switching mechanism between different transporter conformations. Finally, three potential substrate binding sites are predicted for MCT8. CONCLUSIONS: Naturally occurring mutations of MCT8 provide molecular insights into protein regions important for protein folding, substrate binding and the switching mechanism during substrate transport. Future studies guided by this information should help to clarify structure-function relationships at MCT8 which may bear broader relevance for other members of the MCT family. This includes decoding of the complete set of transport-sensitive residue positions and description of structural re-arrangements during transport.
1000 Fächerklassifikation (DDC)
1000 Liste der Beteiligten
1000 Label
1000 Förderer
  1. the graduate college 1208 |
  2. Deutsche Forschungsgemeinschaft |
1000 Fördernummer
  1. TP1 andTP3
  2. KL2334/2-1
1000 Förderprogramm
  1. Hormonal Regulation of Energy Metabolism, Body Weight and Growth
  2. -
1000 Dateien
1000 Förderung
  1. 1000 joinedFunding-child
    1000 Förderer the graduate college 1208 |
    1000 Förderprogramm Hormonal Regulation of Energy Metabolism, Body Weight and Growth
    1000 Fördernummer TP1 andTP3
  2. 1000 joinedFunding-child
    1000 Förderer Deutsche Forschungsgemeinschaft |
    1000 Förderprogramm -
    1000 Fördernummer KL2334/2-1
1000 Objektart article
1000 Beschrieben durch
1000 @id frl:6402722.rdf
1000 Erstellt am 2017-06-01T11:52:23.154+0200
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1000 beschreibt frl:6402722
1000 Bearbeitet von 288
1000 Zuletzt bearbeitet Thu Aug 18 08:02:24 CEST 2022
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1000 Vgl. frl:6402722
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