Significance of the hinge region of the TSHR for receptor activation and hormone binding

Evidence for cooperative signal triggering at the extracellular loops of the TSH receptor

“…2 Correspondence: Leibniz-Institut für Molekulare Pharmakologie, Robert-Rössle-Str.10, D-13125 Berlin, Germany. Email: gkrause@fmp-berlin.de doi: 10.1096/fj.07-104711 tions concerning GPHRs: 1) the involvement of Tyr385 in the C-terminal tail of the TSHR hinge region in hormone binding and signaling (29 -31); 2) the existence and functionality of signaling-relevant epitopes in the N-and C-terminal cysteine boxes of the hinge region (32,33); 3) the recent demonstration that the highly conserved hydrophilic amino acids Glu297 and Glu303 in the N-terminal portion and Asp382 in the C-terminal portion of the hinge region are sensitive for bovine TSH (bTSH) binding and signaling (34); 4) the pathogenicity of an exon 10 deletion in the human LHCGR revealed a significant role for 27 amino acids in the hinge region for hormone-mediated signaling (35,36); 5) superagonistic GPH analogs of the human hormones (37,38) are characterized by additional positively charged amino acids located in peripheral loops of the ␣and ␤-subunits; from the FSHR LRRD/ FSH complex crystal structure (12) and the expected structural homology in other GPHR/GPH complexes, the modified positions of the superagonists would not participate in the LRRD/hormone complex but rather may interact elsewhere, possibly mediating superagonism by interacting with residues in the hinge region; and 6) single mutations in the ECLs that lead to either constitutive activation or to reductions in TSH-induced signaling mediate almost always partial activation or inhibition (39,40).…”