Thyroid-Stimulating Hormone and Thyroid-Stimulating Hormone Receptor Structure-Function Relationships

Abstract

This review focuses on recent advances in the structure-function relationships of thyroid-stimulating hormone (TSH) and its receptor. TSH is a member of the glycoprotein hormone family constituting a subset of the cystine-knot growth factor superfamily. TSH is produced by the pituitary thyrotrophs and released to the circulation in a pulsatile manner. It stimulates thyroid functions using specific membrane TSH receptor (TSHR) that belongs to the superfamily of G protein-coupled receptors (GPCRs). New insights into the structure-function relationships of TSH permitted better understanding of the role of specific protein and carbohydrate domains in the synthesis, bioactivity, and clearance of this hormone. Recent progress in studies on TSHR as well as studies on the other GPCRs provided new clues regarding the molecular mechanisms of receptor activation. Such advances are a result of extensive site-directed mutagenesis, peptide and antibody approaches, detailed sequence analyses, and molecular modeling as well as studies on naturally occurring gain- and loss-of-function mutations. This review integrates expanding information on TSH and TSHR structure-function relationships and summarizes current concepts on ligand-dependent and -independent TSHR activation. Special emphasis has been placed on TSH domains involved in receptor recognition, constitutive activity of TSHR, new insights into the evolution of TSH bioactivity, and the development of high-affinity TSH analogs. Such structural, physiological, pathophysiological, evolutionary, and therapeutic implications of TSH-TSHR structure-function studies are frequently discussed in relation to concomitant progress made in studies on gonadotropins and their receptors.

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“…The released T4 becomes effective once converted peripherally to triiodothyronine (T3) by deiodinase enzymes. The functionally active circulating hormones provide a feedback loop directly to both the hypothalamus and the pituitary suppressing further release of TSH and TRH, thereby maintaining homeostatic control of the hypothalamic-pituitary-thyroid axis (Magner 1989, Szkudlinski et al 2002, Sarapura et al 2011.…”

An update of the pathophysiology of human gonadotrophin subunit and receptor gene mutations and polymorphisms

“…The LH receptor is therefore also known as the LH/CG receptor (gene name: LHCGR). These receptors have a rhodopsinlike transmembrane (TM) domain (Palczewski et al 2000, Themmen & Huhtaniemi 2000, Dias & Van Roey 2001, Ascoli et al 2002, Szkudlinski et al 2002 in common with the superfamily of GPCRs. In addition, they have a large N-terminal extracellular domain (ECD; 359-414 amino acid residues; homology , 40%), which conveys specific hormone binding to the receptors (Braun et al 1991, Cornelis et al 2001, Remy et al 2001.…”

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“…Amongst the very large family of rhodopsin-like G protein-coupled receptors (GPCRs), glycoprotein hormone receptors (GpHRs) constitute a three-member subgroup made up of the follitropin receptor (FSHR) (Dias et al 2002), the lutropin receptor (LH/CGR) (Ascoli et al 2002) and the thyrotropin receptor (TSHR) (Szkudlinski et al 2002). These are themselves part of a subfamily of receptors characterized by an ectodomain containing leucine-rich repeat motifs (LRRs), in addition to the canonical heptahelical serpentine domain typical of GPCRs.…”