Rearrangements in thyroid hormone receptor charge clusters that stabilize bound 3,5′,5-triiodo-L-thyronine and inhibit homodimer formation

Marie Togashi, Phuong Nguyen, Robert Fletterick, John D. Baxter, Paul Webb

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

In this study, we investigated how thyroid hormone (3,5′,5-triiodo-L- thyronine, T3) inhibits binding of thyroid hormone receptor (TR) homodimers, but not TR-retinoid X receptor heterodimers, to thyroid hormone response elements. Specifically we asked why a small subset of TRβ mutations that arise in resistance to thyroid hormone syndrome inhibit both T3 binding and formation of TRβ homodimers on thyroid hormone response elements. We reasoned that these mutations may affect structural elements involved in the coupling of T3 binding to inhibition of TR DNA binding activity. Analysis of TR x-ray structures revealed that each of these resistance to thyroid hormone syndrome mutations affects a cluster of charged amino acids with potential for ionic bond formation between oppositely charged partners. Two clusters (1 and 2) are adjacent to the dimer surface at the junction of helices 10 and 11. Targeted mutagenesis of residues in Cluster 1 (Arg338, Lys342, Asp351, and Asp 355) and Cluster 2 (Arg429, Arg383, and Glu311) confirmed that the clusters are required for stable T 3 binding and for optimal TR homodimer formation on DNA but also revealed that different arrangements of charged residues are needed for these effects. We propose that the charge clusters are homodimer-specific extensions of the dimer surface and further that T3 binding promotes specific rearrangements of these surfaces that simultaneously block homodimer formation on DNA and stabilize the bound hormone. Our data yield insight into the way that T3 regulates TR DNA binding activity and also highlight hitherto unsuspected T3-dependent conformational changes in the receptor ligand binding domain.

Original languageEnglish (US)
Pages (from-to)25665-25673
Number of pages9
JournalJournal of Biological Chemistry
Volume280
Issue number27
DOIs
StatePublished - Jul 8 2005

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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