Histidines in potential substrate recognition sites affect thyroid hormone transport by monocarboxylate transporter 8 (MCT8)

Abstract

Introduction: Mutations in monocarboxylate transporter 8 (MCT8, SLC16A2) cause the Allan-Herndon-Dudley syndrome (AHDS), a severe X-linked psychomotor retardation syndrome. MCT8 belongs to the major facilitator superfamily (MFS) of 12 transmembrane spanning proteins and transports thyroid hormones. Since the phenotype of patients afflicted with AHDS is clinically dissimilar to congenital hypothyroidism, it is speculated that MCT8 transports a critical, yet elusive, additional substrate. A comprehensive understanding of substrate-protein interactions in MCT8 is therefore needed and the goal of this study was to identify individual amino acids along the transport channel cavity which participate in thyroid hormone recognition. Triiodothyronine (T3) is bound between a “His-Arg clamp” in the crystal structure of the T3-receptor/T3 complex.