Leucine at codon 428 in the ninth heptad of thyroid hormone receptor β1 is necessary for interactions with the transcriptional cofactors and functions regardless of dimer formations

Tsuyoshi Monden, Masanobu Yamada, Sumiyasu Ishii, Takeshi Hosoya, Teturo Satoh, Fredric E. Wondisford, Anthony N. Hollenberg, Masatomo Mori

Research output: Contribution to journalArticlepeer-review

Abstract

Structure/function studies of the thyroid hormone receptor (TR) β1 have demonstrated that single amino acid substitutions in either position 428 or 429 in the ligand-binding domain (LBD) can alter heterodimerizations and homodimerizations, respectively. A leucine at 428 is located in a highly conserved region corresponding to the putative ninth heptad repeat of a leucine-zipper-like motif in the LBD of TRβ1. To investigate how the side chain of amino acids at 428 affect receptor characteristics, gel-shift mobility shift assays and yeast two-hybrid assays were analyzed. The neutral status amino acids such as a leucine (wild-type) or a glutamine at 428 preferred heterodimerization with RXR. Furthermore, a positively charged side chain of amino acids at 428 such as an arginine or a lysine, preserved homodimer formation. Irrespective of charge, ninth heptad mutant receptors did not bind the ligand and were not able to interact with either corepressor or coactivating proteins. Limited trypsinization assays revealed no major conformational change in the ninth heptad mutant receptors. Together, these findings suggested that a leucine at 428 was a critical amino acid for both interaction with the thyroid hormone receptor associated proteins and ligand-independent and -dependent functions regardless of dimer formations.

Original languageEnglish (US)
Pages (from-to)427-435
Number of pages9
JournalThyroid
Volume13
Issue number5
DOIs
StatePublished - May 1 2003

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

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