ArticleEndocrinology2013
Histidines in potential substrate recognition sites affect thyroid hormone transport by monocarboxylate transporter 8 (MCT8).
Article in Endocrinology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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13 citing papers in PubMed, 35 citations in OpenAlex.
- Pathogenic MCT8V235L creates a steric clash that is alleviated by a compensating mutation of MCT8F285A.European thyroid journal · 2025Article
- Natural Autoimmunity to the Thyroid Hormone Monocarboxylate Transporters MCT8 and MCT10.Biomedicines · 2021Article
- Acrylamide induces a thyroid allostasis-adaptive response in prepubertal exposed rats.Current research in toxicology · 2020Article
- Membrane-traversing mechanism of thyroid hormone transport by monocarboxylate transporter 8.Cellular and molecular life sciences : CMLS · 2017Article
- New insights into thyroid hormone action.Pharmacology & therapeutics · 2017Review
- Few Amino Acid Exchanges Expand the Substrate Spectrum of Monocarboxylate Transporter 10.Molecular endocrinology (Baltimore, Md.) · 2016Article
- Structural insights into thyroid hormone transport mechanisms of the L-type amino acid transporter 2.Molecular endocrinology (Baltimore, Md.) · 2015Article
- Structure and function of thyroid hormone plasma membrane transporters.European thyroid journal · 2014Review
- Crystal structure of mammalian selenocysteine-dependent iodothyronine deiodinase suggests a peroxiredoxin-like catalytic mechanism.Proceedings of the National Academy of Sciences of the United States of America · 2014Article
- Thyroid hormone signaling in energy homeostasis and energy metabolism.Annals of the New York Academy of Sciences · 2014Review
- Transport of thyroid hormone in brain.Frontiers in endocrinology · 2014Review
- Inherited defects of thyroid hormone-cell-membrane transport: review of recent findings.Current opinion in endocrinology, diabetes, and obesity · 2013Review
- Opening the black box: revealing the molecular basis of thyroid hormone transport.Endocrinology · 2013Article
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4 authors at 3 institutions in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
Mutations in monocarboxylate transporter 8 (MCT8; SLC16A2) cause the Allan-Herndon-Dudley syndrome, a severe X-linked psychomotor retardation syndrome. MCT8 belongs to the major facilitator superfamily of 12 transmembrane-spanning proteins and transports thyroid hormones across the blood-brain barrier and into neurons. How MCT8 distinguishes thyroid hormone substrates from structurally closely related compounds is not known. The goal of this study was to identify critical amino acids along the transport channel cavity, which participate in thyroid hormone recognition. The fact that T3 is bound between a His-Arg clamp in the crystal structure of the T3 receptor/T3 complex prompted us to investigate whether such a motif might potentially be relevant for T3 recognition in MCT8. We therefore replaced candidate histidines and arginines by site-directed mutagenesis and performed activity assays in MDCK-1 cells and Xenopus oocytes. Histidines were replaced by alanine, phenylalanine, and glutamine to probe for molecular properties like aromatic ring structure and H-bonding properties. It was found that some mutations in His192 and His415 significantly changed substrate transport kinetics. Arg301 at the intracellular end of the substrate channel is at an ideal distance to His415 to participate in a His-Arg clamp and mutation to alanine-abrogated hormone transport. Molecular modeling demonstrates a perfect fit of T3 poised into the substrate channel between His415 and Arg301 and observing the same geometry as in the T3 receptor.
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