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Lysine 183 and Glutamic Acid 157 of the TSH Receptor: Two Interacting Residues with a Key Role in Determining Specificity toward TSH and Human CG

Service de Génétique Médicale (G.S., G.V.), Hôpital Erasme, B-1070 Bruxelles, Belgium; Institut de Recherche Interdisciplinaire en Biologie Humaine et Nucléaire (G.S., C.G., I.N., G.V., S.C.), Université Libre de Bruxelles, Campus Erasme, B-1070 Bruxelles, Belgium; Service de Conformation des Macromolécules Biologiques (C.G.), Université Libre de Bruxelles, 1050 Bruxelles, Belgium; Laboratori de Medicina Computacional (L.P.), Unitat de Bioestadística, Facultat de Medicina, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain

Address all correspondence and requests for reprints to: Gilbert Vassart, Institut de Recherche Interdisciplinaire en Biologie Humaine et Nucléaire, Université Libre de Bruxelles, Campus Erasme, 808 route de Lennik, B-1070 Bruxelles, Belgium. E-mail: gvassart{at}ulb.ac.be.

A naturally occuring mutation in the ectodomain of the TSH receptor (TSHr), K183R, has been described recently in a familial case of gestational hyperthyroidism. Hyperthyroidism was explained by the widening of the specificity of the mutant receptor toward human CG (hCG). In the present study, we attempted to understand in molecular terms the structure-phenotype relationships of this mutant in light of the available structural model of TSHr ectodomain established on the template of the atomic structure of the porcine ribonuclease inhibitor. To this aim, we studied by site-directed mutagenesis and functional assays in transfected COS cells the effects of substituting amino acids with different physicochemical properties for lysine 183. Unexpectedly, all TSHr mutants displayed widening of their specificity toward hCG. Molecular dynamics simulations suggested that the gain of function would be secondary to the release of a nearby glutamate residue (E157) from a salt bridge with K183. This hypothesis was supported by further site-directed mutagenesis experiments showing that the presence of an acidic residue in position 157, or in its vicinity, was required to observe the increase in sensitivity to hCG (an acidic residue in position 183 can partially fulfill the role of a free acidic residue in position 157 when tested on the background of a E157A mutant). Our results suggest also that additional natural mutations (especially K183M, N, or Q) in position 183 of TSHr are expected to be found in gestational hyperthyroidism.

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