DNA‐induced unfolding of the thyroid hormone receptor α A/B domain through allostery

Abstract

The A/B domains of nuclear receptors such as thyroid receptor α ( TR α) are considered to be conformationally flexible and can potentially adopt multiple structural conformations. We used intrinsic tryptophan fluorescence quenching and circular dichroism spectroscopy to characterize the unfolding of this A/B domain upon DNA binding to the contiguous DNA‐binding domain ( DBD ). We propose that this allosteric change in A/B domain conformation can allow it to make the multiple interactions with distinct molecular factors of the transcriptional preinitiation complex. We further suggest that by influencing the affinity of the DBD for DNA , A/B domain can fine‐tune the recognition of promotor DNA by TR α.

Non-canonical dimerization of the androgen receptor and other nuclear receptors: implications for human disease

“…2A) (Nadal et al 2017). In multidomain AR, both intra-and interdomain allostery may occur simultaneously (Fernandez et al 2017, Fernandez 2018. The first may take place within the NTD, DBD or LBD moieties, while interdomain signal transduction appears to be essential in coordinating AR functions (e.g., through the well-studied N-C contacts, but also upon as of yet uncharacterized DBD-LBD and LBD-DNA interactions).…”

Allosteric pathways in nuclear receptors — Potential targets for drug design

“…Multiple lines of evidence suggest that the nuclear receptor A/B domains are flexible and can adopt distinct conformations through allostery initiated by DNA:DBD interactions (D. L. Bain, Franden, McManaman, Takimoto, & Horwitz, 2000; David L. Bain, Franden, McManaman, Takimoto, & Horwitz, 2001; Baskakov, et al, 1999; Brodie & McEwan, 2005; Connaghan-Jones, Heneghan, Miura, & Bain, 2007; Fernandez, Gahlot, Rodriguez, & Amburn, 2017; Kumar, Lee, Bolen, & Thompson, 2001; Kumar, et al, 2013; Lavery & McEwan, 2005; McEwan, Lavery, Fischer, & Watt, 2007; Reid, Kelly, Watt, Price, & McEwan, 2002; Simons, Edwards, & Kumar, 2014). A common observation is that the A/B domains in all nuclear receptors studied to date, the DNA-initiated allostery elicits a conformational change in the N-terminal A/B domain (Figure 5).…”

“…This structural flexibility has been proposed to enable the A/B domains to achieve multiple inter-molecular interactions have also been observed for AR (Lavery & McEwan, 2008), GR (Ford, McEwan, Wright, & Gustafsson, 1997; Khan, et al, 2012), PR (Hill, et al, 2012) and TR (Fondell, Brunel, Hisatake, & Roeder, 1996; Fondell, Roy, & Roeder, 1993). Furthermore, the A/B domain observed to fine-tune DNA recognition is finely tuned by the domains flanking the DBD (C domain) (Fernandez, et al, 2017). Thus even subtle changes within these flanking domains (A/B or E/F domains) such as mutations (Helsen, et al, 2012) and molecular interactions with cellular factors (Putcha & Fernandez, 2009) or small-molecule ligands (Chandra, et al, 2008) can affect DNA binding.…”