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PMID: 8395010 Published · ppublish English Comparative Study Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S.

The conserved ninth C-terminal heptad in thyroid hormone and retinoic acid receptors mediates diverse responses by affecting heterodimer but not homodimer formation.

Molecular and cellular biology ·Vol. 13 ·No. 9 ·1993-09-00 ·Pages 5725-37

Au-Fliegner M, Helmer E, Casanova J, Raaka BM, Samuels HH

Abstract

The receptors for thyroid hormone (T3R), all-trans-retinoic acid (RAR), and 9-cis-retinoic acid (RXR) bind DNA response elements as homo- and heterodimers. The ligand-binding domains of these receptors contain nine conserved heptads proposed to play a role in dimerization. Mutant receptors with changes in the first or last hydrophobic amino acids in the highly conserved ninth heptad of chick T3R alpha [cT3R alpha(L365R) and cT3R(L372R)] and human RAR alpha (hRAR alpha) [hRAR(M377R) and hRAR(L384R)] reveal that this heptad is essential for certain heterodimeric interactions and for diverse functional activities. Without ligands, wild-type receptors form both homodimers and heterodimers, while these mutants form only homodimers. Surprisingly, the cognate ligand for each mutant enables heterodimer formation between cT3R(L365R) and RAR or RXR and between hRAR(M377R) and T3R or RXR. Both cT3R(L365R) and hRAR(M377R) mediate ligand-dependent transcriptional regulation. However, unlike the wild-type receptor, non-ligand-associated cT3R(L365R) does not suppress the basal activity of certain promoters containing thyroid hormone response elements, suggesting that this silencing effect of T3R is mediated by unliganded heterodimers of T3R and endogenous RXR or related factors. Heterodimerization is also necessary for the strong ligand-independent inhibition between T3R and RAR on a common response element, since the ninth-heptad mutants function as poor inhibitors. However, with a T3R-specific response element, hRAR(M377R) acts as a retinoic acid-dependent inhibitor of cT3R, indicating the importance of heterodimerization for this inhibition. Our studies also suggest that the ninth heptad is necessary for the dominant inhibition of wild-type T3Rs by mutant T3Rs, as has been found for the thyroid hormone-resistant syndrome in humans. Thus, the ninth heptad repeat is required for heterodimerization, suppression of basal promoter activity, and dominant negative effects of T3R and RAR. Lastly, the finding that cT3R(L365R) and hRAR(M377R) require ligands for heterodimer formation also raises the possibility that heterodimeric interactions are mediated by the ninth heptad without ligands but by a second region of these receptors with ligands.

Related Genes
RAR&agr RAR&bgr RAR&ggr RXR T3R&agr T3R&agr 1 T3R&bgr
MeSH Terms
Amino Acid Sequence Animals Base Sequence Carrier Proteins/chemistry,metabolism DNA Mutational Analysis Gene Expression Regulation Humans Ligands Macromolecular Substances Molecular Sequence Data Promoter Regions, Genetic Protein Binding Protein Conformation Rats Receptors, Cell Surface/chemistry,metabolism Receptors, Retinoic Acid Receptors, Thyroid Hormone/chemistry,metabolism Repressor Proteins/genetics Retinoid X Receptors Sequence Alignment Structure-Activity Relationship Transcription Factors
Chemicals
Carrier Proteins Ligands Macromolecular Substances Receptors, Cell Surface Receptors, Retinoic Acid Receptors, Thyroid Hormone Repressor Proteins Retinoid X Receptors Transcription Factors
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Au-Fliegner M
Department of Medicine, New York University Medical Center, New York 10016.
Helmer E
Casanova J
Raaka B M
Samuels H H
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/mcb.13.9.5725-5737.1993
Published
1993-09-00
Pages
5725-37
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC360309
Subset
IM
Grants
NIDDK NIH HHS · DK-16636 · United States
NIGMS NIH HHS · GM-07308 · United States
NIGMS NIH HHS · GM-07827 · United States
External Links
PubMed source DOI: 10.1128/mcb.13.9.5725-5737.1993 PMC Full Text View journal details
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