Structure and function of the thyroid hormone transporter MCT8

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Mutations in the thyroid hormone transmembrane transport protein MCT8 (monocarboxylate transporter 8) lead to severe psychomotor retardation in patients and are the cause for the Allan- Herndon-Dudley syndrome. It is clear that pathogenic mutations in MCT8 impair thyroid hormone transport activity in vitro. Moreover, patients are characterized by abnormal thyroid hormone levels. However, there is no direct proof that impairment of thyroid hormone transport is the reason for the devastating neurological impairment of the patients. Available evidence is also compatible with the interpretation that mutations in MCT8 impair the transport of another (elusive) substrate and thus lead to metabolic derangements. We are therefore convinced that a better understanding of the biochemical properties of MCT8 is of great importance for new therapeutic attempts. As a starting point, we have already developed a homology model for MCT8 based on the crystal structure of a bacterial transporter and analyzed the substrate spectrum of MCT8 in detail. Guided by the structural model, we have identified important amino acids involved in substrate interactions. By comparison with its close homolog MCT10, we have been able to select only 8 amino acids among which we think are those critical for substrate specificity. We have already prepared a MCT8MCT10 chimeric protein with 4 amino acid changes that behaved more like MCT10 in transport assays. As a step towards an experimental structure and for quantitative kinetic experiments, we want to establish a recombinant expression system in bacteria.