title: Human thyroid receptor forms tetramers in solution, which dissociate into dimers upon ligand binding.
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 TRbeta1 truncation (hTRbeta1deltaAB) 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 hTRbeta1deltaAB 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-hTRbeta1 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.
authors: Instituto de Física de São Carlos, Universidade de São Paulo, São Carlos, SP, Brazil.
authors: Ana C M
authors: AC
authors: Figueira
authors: Sandra M G
authors: SM
authors: Dias
authors: Maria A M
authors: MA
authors: Santos
authors: James W
authors: JW
authors: Apriletti
authors: John D
authors: JD
authors: Baxter
authors: Paul
authors: P
authors: Webb
authors: Francisco A R
authors: FA
authors: Neves
authors: Luiz A
authors: LA
authors: Simeoni
authors: Ralff C J
authors: RC
authors: Ribeiro
authors: Igor
authors: I
authors: Polikarpov