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Genome-wide binding potential and regulatory activity of the glucocorticoid receptor's monomeric and dimeric forms.

ABSTRACT: A widely regarded model for glucocorticoid receptor (GR) action postulates that dimeric binding to DNA regulates unfavorable metabolic pathways while monomeric receptor binding promotes repressive gene responses related to its anti-inflammatory effects. This model has been built upon the characterization of the GRdim mutant, reported to be incapable of DNA binding and dimerization. Although quantitative live-cell imaging data shows GRdim as mostly dimeric, genomic studies based on recovery of enriched half-site response elements suggest monomeric engagement on DNA. Here, we perform genome-wide studies on GRdim and a constitutively monomeric mutant. Our results show that impairing dimerization affects binding even to open chromatin. We also find that GRdim does not exclusively bind half-response elements. Our results do not support a physiological role for monomeric GR and are consistent with a common mode of receptor binding via higher order structures that drives both the activating and repressive actions of glucocorticoids.

SUBMITTER: Johnson TA

PROVIDER: S-EPMC8012360 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Genome-wide binding potential and regulatory activity of the glucocorticoid receptor's monomeric and dimeric forms.

Johnson Thomas A TA Paakinaho Ville V Kim Sohyoung S Hager Gordon L GL Presman Diego M DM

Nature communications 20210331 1

A widely regarded model for glucocorticoid receptor (GR) action postulates that dimeric binding to DNA regulates unfavorable metabolic pathways while monomeric receptor binding promotes repressive gene responses related to its anti-inflammatory effects. This model has been built upon the characterization of the GRdim mutant, reported to be incapable of DNA binding and dimerization. Although quantitative live-cell imaging data shows GRdim as mostly dimeric, genomic studies based on recovery of en ...[more]

PMID: 33790284

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Project description:The F(1)F(0)-adenosine triphosphate (ATP) synthase rotational motor synthesizes most of the ATP required for living from adenosine diphosphate, Pi, and a proton electrochemical gradient across energy-transducing membranes of bacteria, chloroplasts, and mitochondria. However, as a reversible nanomotor, it also hydrolyzes ATP during de-energized conditions in all energy-transducing systems. Thus, different subunits and mechanisms have emerged in nature to control the intrinsic rotation of the enzyme to favor the ATP synthase activity over its opposite and commonly wasteful ATPase turnover. Recent advances in the structural analysis of the bacterial and mitochondrial ATP synthases are summarized to review the distribution and mechanism of the subunits that are part of the central rotor and regulate its gyration. In eubacteria, the epsilon subunit works as a ratchet to favor the rotation of the central stalk in the ATP synthase direction by extending and contracting two alpha-helixes of its C-terminal side and also by binding ATP with low affinity in thermophilic bacteria. On the other hand, in bovine heart mitochondria, the so-called inhibitor protein (IF(1)) interferes with the intrinsic rotational mechanism of the central gamma subunit and with the opening and closing of the catalytic beta-subunits to inhibit its ATPase activity. Besides its inhibitory role, the IF(1) protein also promotes the dimerization of the bovine and rat mitochondrial enzymes, albeit it is not essential for dimerization of the yeast F(1)F(0) mitochondrial complex. High-resolution electron microscopy of the dimeric enzyme in its bovine and yeast forms shows a conical shape that is compatible with the role of the ATP synthase dimer in the formation of tubular the cristae membrane of mitochondria after further oligomerization. Dimerization of the mitochondrial ATP synthase diminishes the rotational drag of the central rotor that would decrease the coupling efficiency between rotation of the central stalk and ATP synthesis taking place at the F(1) portion. In addition, F(1)F(0) dimerization and its further oligomerization also increase the stability of the enzyme to natural or experimentally induced destabilizing conditions.

Dataset Information

Genome-wide binding potential and regulatory activity of the glucocorticoid receptor's monomeric and dimeric forms.

Publications

Genome-wide binding potential and regulatory activity of the glucocorticoid receptor's monomeric and dimeric forms.

Similar Datasets

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