Abstract
The precise mechanism by which glucocorticoid receptor (GR) regulates the transcription of its target genes is largely unknown. This is, in part, due to the lack of structural and functional information about GR's N-terminal activation function domain, AF1. Like many steroid hormone receptors (SHRs), the GR AF1 exists in an intrinsically disordered (ID) conformation or an ensemble of conformers that collectively appears to be unstructured. The GR AF1 is known to recruit several coregulatory proteins, including those from the basal transcriptional machinery, e.g., TATA box binding protein (TBP) that forms the basis for the multiprotein transcription initiation complex. However, the precise mechanism of this process is unknown. We have earlier shown that conditional folding of the GR AF1 is the key for its interactions with critical coactivator proteins. We hypothesize that binding of TBP to AF1 results in the structural rearrangement of the ID AF1 domain such that its surfaces become easily accessible for interaction with other coactivators. To test this hypothesis, we determined whether TBP binding-induced structure formation in the GR AF1 facilitates its interaction with steroid receptor coactivator-1 (SRC-1), a critical coactivator that is important for GR-mediated transcriptional activity. Our data show that stoichiometric binding of TBP induces significantly higher helical content at the expense of random coil configuration in the GR AF1. Further, we found that this induced AF1 conformation facilitates its interaction with SRC-1, and subsequent AF1-mediated transcriptional activity. Our results may provide a potential mechanism through which GR and by large other SHRs may regulate the expression of the GR-target genes.
Highlights
Ligand-activated glucocorticoid receptor (GR) regulates transcription of target genes by binding to DNA at specific hormone response elements and by interacting with other coregulatory proteins [1], [2], [3], [4], [5]
Our results provide a potential mechanism through which GR and other steroid hormone receptors (SHRs) may regulate the expression of the GR-target genes, information essential to understand how specific signals are passed from the receptor to target genes
These results were further confirmed from the Predictor of Naturally Disordered Regions (PONDR) Scores obtained as a function of cumulative fraction of residues (Figure 2D) in which the black line plot separates the boundary of database proteins that possess globular structure
Summary
Ligand-activated glucocorticoid receptor (GR) regulates transcription of target genes by binding to DNA at specific hormone response elements and by interacting with other coregulatory proteins [1], [2], [3], [4], [5]. Like other members of the steroid hormone receptors (SHRs), the GR possesses a modular structure characterized by three major functional domains: N-terminal domain (NTD), DNA binding domain (DBD), and ligand binding domain (LBD) (Figure 1A). The precise mechanism by which SHRs regulate the transcription of the target genes is largely unknown. This is, in part, due to the lack of structural and functional information about AF1 domain. Due to availability of the LBD crystal structure [15], the relevant structural and functional properties of AF2 have been well characterized whereas it is nebulous in the case of AF1
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
