Pathological Interactions Between Mutant Thyroid Hormone Receptors and Corepressors and Their Modulation by a Thyroid Hormone Analogue with Therapeutic Potential

Author(s)

Harrus, Deborah ^{[1, 2]} ; Demene, Helene ^[1] ; Vasquez, Edwin ^[3] ; Boulahtouf, Abdelhay ^[4] ; Germain, Pierre ^[1] ; Figueira, Ana Carolina ^[3] ; Privalsky, Martin L. ^[5] ; Bourguet, William ^[1] ; le Maire, Albane ^{[3, 1]}

Affiliation

^[1] Univ Montpellier, CBS, CNRS, INSERM, Montpellier - France

^[2] Univ Oulu, Fac Biochem & Mol Med, Oulu - Finland

^[3] Brazilian Ctr Res Energy & Mat CNPEM, Brazilian Biosci Natl Lab LNBio, Campinas, SP - Brazil

^[4] Univ Montpellier, IRCM, INSERM, ICM, Montpellier - France

^[5] Univ Calif Davis, Coll Biol Sci, Dept Microbiol & Mol Genet, Davis, CA 95616 - USA

• Document type: Journal article
• Source: THYROID; v. 28, n. 12 OCT 2018.
• Web of Science Citations: 4

Abstract

Background: Thyroid hormone receptors (TRs) are tightly regulated by the corepressors nuclear receptor corepressor (NCoR) and silencing mediator of retinoic acid and thyroid hormone receptors. Three conserved corepressor/NR signature box motifs (CoRNR1-3) forming the nuclear receptor interaction domain have been identified in these corepressors. Whereas TRs regulate multiple normal physiological and developmental pathways, mutations in TRs can result in endocrine diseases and be associated with cancers due to impairment of corepressor release. Three mutants that are located in helix H11 of TRs are of special interest: TR alpha-M388I, a mutant associated with the development of renal clear cell carcinomas (RCCCs), and TR beta-Delta 430 and TR beta-Delta 432, two deletion mutants causing resistance to thyroid hormone syndrome. Methods: Several cell-based and biophysical methods were used to measure the affinity between wild-type and mutant TR alpha and TR beta and all the CoRNR motifs from corepressors to quantify the effects of different thyroid hormone analogues on these interactions. This study was coupled with the measurement of interactions between wild-type and mutant TRs in the context of a heterodimer with RXR to a NCoR fragment in the presence of the same ligands. Structural insights into the binding mode of corepressors to TRs were assessed in parallel by nuclear magnetic resonance spectroscopy. Results: The study shows that TRs interact more avidly with the silencing mediator of retinoic acid and thyroid hormone receptors than with NCoR peptides, and that TR alpha binds most avidly to S-CoRNR3, whereas TR beta binds preferentially to S-CoRNR2. In the studied TR mutants, a transfer of the CoRNR-specificity toward CoRNR1 was observed, coupled with a significant increase in the binding strength. In contrast to 3,5,3-triiodothyronine (T3), the agonist TRIAC and the antagonist NH-3 were very efficient at dissociating the abnormally strong interactions between mutant TR beta s and corepressors. A strong impairment of T3-binding for TR beta mutants was shown compared to TRIAC and NH-3 and could explain the different efficiencies of the different ligands in releasing corepressors from the studied TR beta mutants. Consequently, TRIAC was found to be more effective than T3 in facilitating coactivator recruitment and decreasing the dominant activity of TR beta-Delta 430. Conclusion: This study helps to clarify the specific interaction surfaces involved in the pathologic phenotype of TR mutants and demonstrates that TRIAC is a potential therapeutic agent for patients suffering from resistance to thyroid hormone syndromes. (AU)

• FAPESP's process: 16/15986-7 - structural studies of the interaction of normal and pathological THR with corepressors
• Grantee: Edwin Fernando Vásquez Vásquez
• Support Opportunities: Scholarships in Brazil - Master