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The mineralocorticoid receptor forms higher order oligomers upon DNA binding

The prevailing model of steroid hormone nuclear receptor function assumes ligand-induced homodimer formation followed by binding to DNA hormone response elements (HREs). This model has been challenged by evidence showing that the glucocorticoid receptor (GR) forms tetramers upon ligand and DNA bindi...

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Autores principales: Fettweis, Gregory, Johnson, Thomas A., Almeida-Prieto, Brian, Presman, Diego M., Hager, Gordon L., Alvarez de la Rosa, Diego
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9928021/
https://www.ncbi.nlm.nih.gov/pubmed/36789424
http://dx.doi.org/10.1101/2023.01.26.525752
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author Fettweis, Gregory
Johnson, Thomas A.
Almeida-Prieto, Brian
Presman, Diego M.
Hager, Gordon L.
Alvarez de la Rosa, Diego
author_facet Fettweis, Gregory
Johnson, Thomas A.
Almeida-Prieto, Brian
Presman, Diego M.
Hager, Gordon L.
Alvarez de la Rosa, Diego
author_sort Fettweis, Gregory
collection PubMed
description The prevailing model of steroid hormone nuclear receptor function assumes ligand-induced homodimer formation followed by binding to DNA hormone response elements (HREs). This model has been challenged by evidence showing that the glucocorticoid receptor (GR) forms tetramers upon ligand and DNA binding, which then drive receptor-mediated gene transactivation and transrepression. GR and the closely-related mineralocorticoid receptors (MR) interact to transduce corticosteroid hormone signaling, but whether they share the same quaternary arrangement is unknown. Here, we used a fluorescence imaging technique, Number & Brightness, to study oligomerization in a cell system allowing real-time analysis of receptor-DNA interactions. Agonist-bound MR forms tetramers in the nucleoplasm and higher order oligomers upon binding to HREs. Antagonists form intermediate quaternary arrangements, suggesting that large oligomers are essential for function. Divergence between MR and GR quaternary structure is driven by different functionality of known and new multimerization interfaces, which does not preclude formation of heteromers. Thus, influencing oligomerization may be important to selectively modulate corticosteroid signaling.
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spelling pubmed-99280212023-02-15 The mineralocorticoid receptor forms higher order oligomers upon DNA binding Fettweis, Gregory Johnson, Thomas A. Almeida-Prieto, Brian Presman, Diego M. Hager, Gordon L. Alvarez de la Rosa, Diego bioRxiv Article The prevailing model of steroid hormone nuclear receptor function assumes ligand-induced homodimer formation followed by binding to DNA hormone response elements (HREs). This model has been challenged by evidence showing that the glucocorticoid receptor (GR) forms tetramers upon ligand and DNA binding, which then drive receptor-mediated gene transactivation and transrepression. GR and the closely-related mineralocorticoid receptors (MR) interact to transduce corticosteroid hormone signaling, but whether they share the same quaternary arrangement is unknown. Here, we used a fluorescence imaging technique, Number & Brightness, to study oligomerization in a cell system allowing real-time analysis of receptor-DNA interactions. Agonist-bound MR forms tetramers in the nucleoplasm and higher order oligomers upon binding to HREs. Antagonists form intermediate quaternary arrangements, suggesting that large oligomers are essential for function. Divergence between MR and GR quaternary structure is driven by different functionality of known and new multimerization interfaces, which does not preclude formation of heteromers. Thus, influencing oligomerization may be important to selectively modulate corticosteroid signaling. Cold Spring Harbor Laboratory 2023-06-14 /pmc/articles/PMC9928021/ /pubmed/36789424 http://dx.doi.org/10.1101/2023.01.26.525752 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
spellingShingle Article
Fettweis, Gregory
Johnson, Thomas A.
Almeida-Prieto, Brian
Presman, Diego M.
Hager, Gordon L.
Alvarez de la Rosa, Diego
The mineralocorticoid receptor forms higher order oligomers upon DNA binding
title The mineralocorticoid receptor forms higher order oligomers upon DNA binding
title_full The mineralocorticoid receptor forms higher order oligomers upon DNA binding
title_fullStr The mineralocorticoid receptor forms higher order oligomers upon DNA binding
title_full_unstemmed The mineralocorticoid receptor forms higher order oligomers upon DNA binding
title_short The mineralocorticoid receptor forms higher order oligomers upon DNA binding
title_sort mineralocorticoid receptor forms higher order oligomers upon dna binding
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9928021/
https://www.ncbi.nlm.nih.gov/pubmed/36789424
http://dx.doi.org/10.1101/2023.01.26.525752
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