Abstract
BackgroundThe 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.MethodsWe 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.ResultsWe 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.ConclusionsNaturally 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.
Highlights
The Allan-Herndon-Dudley syndrome is an X-linked mental retardation first described in 1944 [1]
In this study we started with the hypothesis that two specific charged amino acids in the transmembrane region (R4458.50 and D49810.49) may interact with the amino acid backbone of iodothyronines
These findings support our assumption that both amino acids are important for substrate transport
Summary
The Allan-Herndon-Dudley syndrome is an X-linked mental retardation first described in 1944 [1]. It is assumed that substrate binding by MFS transporters triggers the transition between an “outside-open” and “inside-open” conformation, the so-called “rockerswitch” model [8,9] This structural movement must be linked with specific intramolecular events like rearrangement of amino acid interactions and with substrate trans-localization. Despite the need of more supporting and detailed information for this structuralfunctional “rocker-switch” model, specific substrate-protein interactions need to be considered as to be causally related to different protein conformations. MCT8 mutations are the underlying cause of a syndrome of severe Xlinked 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. More than 25 pathogenic mutations in hMCT8 are known and they are valuable indicators of important regions for structural and functional MCT8 properties
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