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Medical Department (M.C., H.J., R.P.), University of Leipzig, D-04103 Leipzig, Germany; Forschungsinstitut fuer Molekulare Pharmakologie (G.Kl., G.Kr.), D-13125 Berlin, Germany; and National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases (S.N.), Bethesda, Maryland 20814
Address all correspondence and requests for reprints to: Ralf Paschke, M.D., Medical Department, University of Leipzig, Philipp-Rosenthal-Strasse 27, 04103 Leipzig, Germany. E-mail: pasr{at}medizin.uni-leipzig.de.
Previous reports on the follicle-stimulating hormone receptor and choriogonadotropic/LH receptor, which belong to the glycoprotein hormone receptor family, suggest that the extracellular loop (ECL) 3 could be a key domain for ligand binding and intramolecular receptor signaling. In contrast to ECLs 1 and 2 of glycoprotein hormone receptors, the ECL3 displays high sequence homology, particularly in the central portion of the loop. Therefore, we opted to identify amino acids with functional importance within ECL3 of the TSH receptor (TSHR). Single alanine substitutions of all residues in ECL3 were generated. Functional characterization revealed the importance of five amino acids in the central portion of ECL3 and K660 at the ECL3/transmembrane helix (TMH) 7 junction for TSHR signaling. Decrease of Gs activation and loss of Gq activation by substitutions of K660 demonstrates a role for this position for TSHR conformation and signal transduction. By molecular modeling, we predicted potential interaction partners of K660:E409 and D410 in the N terminus of TMH1 and D573 in the ECL2. Complementary double mutants did not reconstitute Gs/Gq-mediated signaling, suggesting that K660 is not directly involved in a structural unit between ECL3 and the N terminus of TMH1. These results support a TSHR model in which the side chain of K660 is orientated toward the backbone of ECL2. Moreover, our findings provide evidence that a hydrophobic cluster, comprising residues 652–656 of ECL3, strongly influences intramolecular signal transduction and G protein activation of the TSHR.
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