Variable steroid receptor responses: Intrinsically disordered AF1 is the key

Abstract

Steroid hormones, acting through their cognate receptor proteins, see widespread clinical applications due to their ability to alter the induction or repression of numerous genes. However, steroid usage is limited by the current inability to control off-target, or non-specific, side-effects. Recent results from three separate areas of research with glucocorticoid and other steroid receptors (cofactor-induced changes in receptor structure, the ability of ligands to alter remote regions of receptor structure, and how cofactor concentration affects both ligand potency and efficacy) indicate that a key element of receptor activity is the intrinsically disordered amino-terminal domain. These results are combined to construct a novel framework within which to logically pursue various approaches that could afford increased selectivity in steroid-based therapies.

Keywords: A(max) and EC(50); AF1 domain as a molecular rheostat; Intrinsically disordered domains; Selective receptor modulators (SRMs); Selectivity in controlling gene expression; Steroid receptors.

Fig. 1

Model for control of cell- and gene-selective transactivation with agonists and SRMs of SRs. Ligand-free SR without chaperone proteins is represented as a three-domain protein consisting of LBD, DBD, and unstructured (red, unlabeled) N-terminal ID/AF1 domains. Ligand (colored geometric shapes) binding modifies LBD conformation and the complex binds to its hormone response element (HRE) on chromatin to form a dimer (only one monomer is illustrated). Gene-selective variations can arise both from near-by or distant interacting, DNA-associated transcription factors (one proximal factor is illustrated; dark blue striped box and shaded oval) (Metivier et al., 2006; Datson et al., 2011; Altintas et al., 2012) and from HRE-induced conformational changes (not shown) (Meijsing et al., 2009; Kim et al., 2013). Differences in cellular concentrations of cofactors (solid shapes), which then bind either simultaneously (as shown) or separately (not illustrated) to the ID/AF1 and LBD to induce varied ID/AF1 structures (different shaped colored ellipses), could yield cell-selective responses. Additional possibilities at this, and the previous step, are indicated by arrows pointing to undesignated structures (…) and subsequent steps. The resultant receptor/steroid/cofactor complexes can then uniquely interact with other transcriptional machinery components to afford varied transcriptional responses. Not indicated are perturbations due to further influences such as protein alterations (e.g., phosphorylation, acetylation, and sumoylation), epigenetic modifications, and other factors/molecules interacting with the receptor and/or illustrated cofactors. SR-mediated gene repression would involve a parallel set of possibilities starting, in most cases, with tethered SR complexes. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)