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Allostery in Nuclear Hormone Receptor Transactivation
Author(s) -
Fernandez Elias John
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.lb68
Subject(s) - coactivator , transactivation , nuclear receptor coactivator 1 , nuclear receptor , retinoid x receptor , allosteric regulation , chemistry , microbiology and biotechnology , biophysics , cooperative binding , nuclear receptor coactivator 2 , biochemistry , transcription factor , receptor , binding site , biology , gene
Nuclear hormone receptors (NR) relay cellular signals through distinct multiprotein assemblies. Hormonal signals produce structural changes within NRs that determine the composition of the interacting proteins. NRs are characteristically modular proteins. At the N terminus is the DNA‐binding domain (DBD). The ligand‐binding domain (LBD) contains a dimerization interface that associates with the retinoid X receptor (RXR) and a C‐terminal ligand‐dependent transactivation domain (AF2). Agonist binding results in conformational changes associated with a transcriptionally active state where the AF2 domain rearranges along the receptor surface creating a docking site for coactivator proteins such as the steroid receptor coactivator 1 (SRC1). Using the constitutive androstane (CAR) and thyroid hormone receptors (TR) as typical NR systems, we propose models for allostery within NRs that address the following questions: (i) What role do ligands play in the stoichiometric assembly of the NR:coregulator complex? (ii) How do discrete sites regulate the activity of these receptors? (iii) How do the DBD and LBD communicate to regulate coactivator and DNA recognition? With biophysical and cell‐based transcription assays (PMID:25053412; 22474364; 19561066) we report (1) that agonist ligands can potentiate transactivation through both coactivator‐binding sites on CAR:RXR, which distinctly bind two SRC1 molecules; (2) on the structural basis for negative cooperativity between the TR and RXR ligand‐binding pockets in TR:RXR. We also propose a novel ‘frustrated fit’ allosteric mechanism (PMID: 25658131 & 27110634) and (3) on quantitative evidence of direct, DNA‐dependent, communication between the DBD and LBD.