The helix 1–3 loop in the glucocorticoid receptor LBD is a regulatory element for FKBP cochaperones

Cluning, Carmel; Ward, Bryan K.; Rea, Sarah L.; Arulpragasam, Ajanthy; Fuller, Peter J.; Ratajczak, Thomas

doi:10.1210/me.2012-1023

Cited by 26Heat shock proteins researchEstrogen and related hormone effectsReceptor Mechanisms and Signaling

The helix 1–3 loop in the glucocorticoid receptor LBD is a regulatory element for FKBP cochaperones

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Cluning, Carmel, Ward, Bryan K., Rea, Sarah L., Arulpragasam, Ajanthy, Fuller, Peter J., Ratajczak, Thomas·2013·Molecular Endocrinology

DOI 10.1210/me.2012-1023PMC PMC5415241

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Abstract

The heat-shock protein 90 (Hsp90) cochaperone FK506-binding protein 52 (FKBP52) upregulates, whereas FKBP51 inhibits, hormone binding and nuclear targeting of the glucocorticoid receptor (GR). Decreased cortisol sensitivity in the guinea pig is attributed to changes within the helix 1 to helix 3 (H1-H3) loop of the guinea pig GR (gpGR) ligand-binding domain. It has been proposed that this loop serves as a contact point for FKBP52 and/or FKBP51 with receptor. We examined the role of the H1-H3 loop in GR activation by FKBP52 using a Saccharomyces cerevisiae model. The activity of rat GR (rGR) containing the gpGR H1-H3 loop substitutions was still potentiated by FKBP52, confirming the loop is not involved in primary FKBP52 interactions. Additional assays also excluded a role for other intervening loops between ligand-binding domain helices in direct interactions with FKBP52 associated with enhanced receptor activity. Complementary studies in FKBP51-deficient mouse embryo fibroblasts and HEK293 cells demonstrated that substitution of the gpGR H1-H3 loop residues into rGR dramatically increased receptor repression by FKBP51 without enhancing receptor-FKBP51 interaction and did not alter recruitment of endogenous Hsp90 and the p23 cochaperone to receptor complexes. FKBP51 suppression of the mutated rGR did not require FKBP51 peptidylprolyl cis-trans isomerase activity and was not disrupted by mutation of the FK1 proline-rich loop thought to mediate reciprocal FKBP influences on receptor activity. We conclude that the gpGR-specific mutations within the H1-H3 loop confer global changes within the GR-Hsp90 complex that favor FKBP51 repression over FKBP52 potentiation, thus identifying the loop as an important target for GR regulation by the FKBP cochaperones.

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The Helix 1-3 (H1-H3) loop in the GR LBD is important for FKBP regulation and may represent an FKBP52 regulatory site.
“In support of this idea, recent studies suggest that the Helix 1–3 (H1-H3) loop in the GR LBD is important for FKBP regulation and may represent an FKBP52 regulatory site [32].”
From The FKBP52 Cochaperone Acts in Synergy with β-Catenin to Potentiate Androgen Receptor Signaling (2015) · cites this paper as [32]
A direct binding interaction between FKBP51/FKBP52 and the steroid receptor proteins has not been demonstrated.
“Specific binding interactions between FKBP51/FKBP52 and the steroid receptor proteins have been proposed, including the BF-3 (binding function 3) regulatory site [14] and the H1–H3 loop [15] of the ligand-binding domain, although a direct binding interaction has not been demonstrated [16].”
From Differential conformational dynamics in the closely homologous FK506-binding domains of FKBP51 and FKBP52 (2014) · cites this paper as [16]

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Background
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Result

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Authors: Cluning, C., Ward, B. K., Rea, S. L., Arulpragasam, A., Fuller, P. J., & Ratajczak, T.
Affiliations: The University of Western Australia (AU)
Prince Henry's Institute of Medical Research (P.J.F.), Clayton, Victoria 3168, Australia
Corresponding author: Ratajczak, Thomas
ORCID: Ward, Bryan K.
Rea, Sarah L.
Fuller, Peter J.
Venue: Molecular Endocrinology
Publisher: The Endocrine Society
Published: 2013-07-01
Volume: 27
Issue: 7
Pages: 1020-1035
ISSN: 0888-8809 (ISSN-L)
1944-9917
DOI: 10.1210/me.2012-1023
PMC: PMC5415241
OpenAlex: W1977435913
Cited by: 26
References: 102
Citations by year: 2024: 1 · 2023: 5 · 2022: 3 · 2021: 1 · 2020: 1 · 2019: 3 · 2018: 2 · 2017: 1 · 2016: 1 · 2015: 5 · 2014: 3
FWCI: 1.34
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Molecular Endocrinology (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Murdoch University Research Portal (submittedVersion)
UWA Profiles and Research Repository (UWA) (submittedVersion)
eSpace (Curtin University) (submittedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
Keywords: glucocorticoid receptor, ligand-binding domain, FKBP52, FKBP51, Hsp90 co-chaperone, receptor activation, HSP90
MeSH terms: Tacrolimus Binding Protein 5, Amino Acid Sequence, Animals, Guinea Pigs, HeLa Cells, Humans, Models, Biological, Molecular Sequence Data, Mutation, Proline, Receptors, Androgen, Receptors, Glucocorticoid, Regulatory Sequences, Nucleic Acid, Saccharomyces cerevisiae, Structure-Activity Relationship, Conserved Sequence, Protein Structure, Secondary, Protein Structure, Tertiary, Tacrolimus Binding Proteins, Mutant Proteins, Mice, Rats, Sterol Regulatory Element Binding Protein 1, HEK293 Cells

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The helix 1–3 loop in the glucocorticoid receptor LBD is a regulatory element for FKBP cochaperones

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