ECE2016 Symposia Hitchhiker's guide to the microsmos of GPCRs (3 abstracts)
Glycoprotein hormone receptors (GPHRs) have been cloned about 25 years ago and, since then, the glycoprotein hormones TSH, LH/hCG and FSH are considered as the agonists for their respective receptors. Additionally to TSH, the TSH receptor for example, can be activated by mutations and autoantibodies causing hyperthyroidism and Graves disease, respectively. The mode, how the receptors integrate the activating actions of glycoprotein hormones, mutations and autoantibodies to trigger receptors signal transduction, is a still unsolved mystery. We recently showed that a short peptide sequence in the C-terminal part of the extracellular N terminus functions as a tethered agonist for all glycoprotein hormone receptors in vitro and in vivo. Our data support a scenario where, upon structural changes within the ectodomain due to extracellular ligand binding, this intramolecular ligand most probably isomerizes and activates the 7-transmembrane helix domain triggering G-protein activation. The identification of the internal agonist sequence for GPHRs now allows for characterization of its agonist binding pocket followed by rational ligand design. Such ligands could be therapeutically useful for blocking TSHR activation due to autoantibodies in Graves disease and activating mutations in GPHRs.