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J Biol Chem, Vol. 273, Issue 17, 10270-10278, April 24, 1998

A Novel Multifunctional Motif in the Amino-terminal A/B Domain of T₃R Modulates DNA Binding and Receptor Dimerization

Emir Hadzic, Ioanis Habeos, Bruce M. Raaka, and Herbert H. Samuels

From the Division of Molecular Endocrinology, Departments of Medicine and Pharmacology, and the  Department of Cell Biology, New York University Medical Center, New York, New York 10016

We reported previously that deletion of the 50-amino acid NH₂-terminal A/B domain of the chicken (c) or rat thyroid hormone (T₃) receptor- (T₃R) decreased the T₃-dependent stimulation of genes regulated by native thyroid hormone response elements (TREs). This requirement of the NH₂-terminal A/B domain for transcriptional activation was mapped to amino acids 21-30 of cT₃R. Expression of transcription factor IIB (TFIIB) in cells was shown to enhance T₃-dependent transcriptional activation by cT₃R, and this enhancement by TFIIB was dependent on the same 10-amino acid sequence. In vitro binding studies indicated that cT₃R interacts efficiently with TFIIB, and this interaction requires amino acids ²³KRKRK²⁷ in the A/B domain. In this study we document the functional importance of these five basic residues in transcriptional activation by cT₃R, further supporting the biological significance of these residues and their interaction with TFIIB. Interestingly, we also find that the same amino acids also affect DNA binding and dimerization of cT₃R. Gel mobility shift assays reveal that a cT₃R mutant that has all five basic amino acids changed from ²³KRKRK²⁷ to ²³TITIT²⁷ binds to a palindromic TRE predominantly as a homodimer, whereas cT₃R with the wild-type ²³KRKRK²⁷ sequence binds predominantly as a monomer. This results from both a marked decrease in the ability of the cT₃R mutant to bind as a monomer and from an enhanced ability to dimerize as reflected by an increase in DNA-bound T₃R-retinoic X receptor heterodimers. These effects of ²³KRKRK²⁷ on DNA binding, dimerization, transcriptional activation, and the association of T₃R with TFIIB support the notion that this basic amino acid motif may influence the overall structure and function of T₃R and, thus, play a role in determining the distinct context-dependent transactivation potentials of the individual T₃R isoforms.

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