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

Molecular Endocrinology
Guillaume SmitsSabine Costagliola

Abstract

A naturally occurring 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 positi...Continue Reading

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Citations

Aug 3, 2005·The Journal of Clinical Investigation·Terry F DaviesRauf Latif
May 26, 2004·Best Practice & Research. Clinical Endocrinology & Metabolism·Jerome M Hershman
Oct 21, 2016·Journal of Obstetrics and Gynaecology : the Journal of the Institute of Obstetrics and Gynaecology·Eunice López-MuñozOlivia Sánchez-Rodríguez
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Dec 12, 2018·Protein and Peptide Letters·Norio MatsushimaRobert H Kretsinger
Oct 24, 2006·Molecular and Cellular Endocrinology·J Bogerd

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