Human thyroid receptor forms tetramers in solution, which dissociate into dimers upon ligand binding

Ana C.M. Figueira, Sandra M.G. Dias, Maria A.M. Santos, James W. Apriletti, John D. Baxter, Paul Webb, Francisco A.R. Neves, Luiz A. Simeoni, Ralff C.J. Ribeiro, Igor Polikarpov

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

Thyroid hormone nuclear receptors (TRs) bind to DNA and activate transcription as heterodimers with the retinoid X receptor (RXR) or as homodimers or monomers. RXR also binds to DNA and activates transcription as homodimers but can, in addition, self-associate into homotetramers in the absence of ligand and DNA templates. It is thought that homotetramer formation serves to sequester excess RXRs into an inactive pool within the cell. Here, we report systematic studies of the multimeric state of a recombinant human TRβ1 truncation (hTRβ1ΔAB) that encompasses the complete DNA binding domain and ligand binding domain in solution. Native gel electrophoresis, chemical crosslinking, gel filtration, and dynamic light scattering experiments reveal that hTRβ1ΔAB forms a mixture of monomers, dimers, and tetramers. Like RXR, increasing protein concentration shifts the equilibrium between TR multimers toward tetramer formation, whereas binding of cognate thyroid hormone leads to dissociation of tetramers and increased formation of dimers. This work represents the first evidence that apo-hTRβ1 forms homotetramers. The findings raise the possibility that tetramer formation provides an additional, and previously unsuspected, level of control of TR activity and that the capacity for homotetramer formation may be more widespread in the nuclear receptor family than previously thought.

Original languageEnglish (US)
Pages (from-to)453-462
Number of pages10
JournalCell biochemistry and biophysics
Volume44
Issue number3
DOIs
StatePublished - May 31 2006

Keywords

  • Dissociation
  • Ligand binding
  • Nuclear receptor
  • Oligomerization
  • Tetramerization

ASJC Scopus subject areas

  • Cell Biology
  • Clinical Biochemistry
  • Biophysics
  • Biochemistry

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