Ligand-Induced Stability Studies at the TSH Receptor Show the Linking Region to be a Chameleon

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ID: 326665
2026
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Abstract
Glycoprotein hormone receptors (GPHRs) share a conserved architecture but the thyroid-stimulating hormone receptor (TSHR) is unique in possessing a large 141-amino-acid region called the hinge or linking region (LR) that contains a 50-amino-acid post translational cleavage site. Our previous computational modeling of the full-length TSHR identified this LR as an intrinsically disordered protein (IDP) that appears to serve as a critical bridge transmitting structural changes from the leucine-rich domain (LRD) to the transmembrane domain (TMD) of the receptor during its activation. However, the behavior of the LR in response to different ligands that bind the LRD and its influence on receptor structure as a whole has not been systematically explored. Using molecular dynamic simulations of full-length TSHR complexes with various ligands, we have examined the influence of ligand on TSHR structural changes with a first emphasis on those adopted by the LR upon ligand binding. Our analyses revealed that the LR did not maintain a stable secondary or tertiary structure in isolation but exhibited high conformational flexibility, adopting distinct structures depending on the bound ligand-i.e., it is a chameleon. Notably, a β-sheet structure was absent only in the complex with a TSHR blocking antibody (K1-70) and not with stimulating (M22) or LR-specific (MC1) antibodies. Furthermore, using a TSHR fragment (V1.3), absent the LR, when subjected to protein thermal shift analyses, we showed that TSH ligand was able to influence the entire TSHR structure and, therefore, not just the LR.
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openalex_W7204437221 Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Mihaly Mezei, Rauf Latif, Pingping Xiang, Terry F. Davies
Journal american journal of physiology endocrinology and metabolism
Year 2026
DOI
10.1210/endocr/bqag099
URL
https://doi.org/10.1210/endocr/bqag099
Keywords Keywords not found

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