Analysis of the roles of mutations system in thyroid hormone receptor- beta by a bacterial biosensor system

• Published in: Journal of molecular endocrinology Vol. 52; no. 1; p. 1
• Main Authors: Shi, Changhua, Meng, Qing, Wood, David W
• Format: Journal Article
• Language: English
• Published: 01.02.2014
• Subjects: Bacteria
• ISSN: 0952-5041; 1479-6813

Mutations in thyroid hormone receptors (TRs) often lead to metabolic and developmental disorders, but patients with these mutations are difficult to treat with existing thyromimetic drugs. In this study, we analyzed six clinically observed mutations in the ligand-binding domain of the human TR beta using an engineered bacterial hormone biosensor. Six agonist compounds, including triiodothyronine (T sub(3)), thyroxine (T sub(4)), 3,5,3'-triiodothyroacetic acid (Triac), GC-1, KB-141, and CO-23, and the antagonist NH-3 were examined for their ability to bind to each of the TR beta mutants. The results indicate that some mutations lead to the loss of ability to bind to native ligands, ranging from several fold to several hundred fold, while other mutations completely abolish the ability to bind to any ligand. Notably, the effect of each ligand on each TR beta mutant in this bacterial system is highly dependent on both the mutation and the ligand; some ligands were bound well by a wide variety of mutants, while other ligands lost their affinity for all but the WT receptor. This study demonstrates the ability of our bacterial system to differentiate agonist compounds from antagonist compounds and shows that one of the TR beta mutations leads to an unexpected increase in antagonist ability relative to other mutations. These results indicate that this bacterial sensor can be used to rapidly determine ligand-binding ability and character for clinically relevant TR beta mutants.