Hsp70 and Hsp40 inhibit an inter-domain interaction necessary for transcriptional activity in the androgen receptor
Open accessAbstract
Molecular chaperones such as Hsp40 and Hsp70 hold the androgen receptor (AR) in an inactive conformation. They are released in the presence of androgens, enabling transactivation and causing the receptor to become aggregation-prone. Here we show that these molecular chaperones recognize a region of the AR N-terminal domain (NTD), including a FQNLF motif, that interacts with the AR ligand-binding domain (LBD) upon activation. This suggests that competition between molecular chaperones and the LBD for the FQNLF motif regulates AR activation. We also show that, while the free NTD oligomerizes, binding to Hsp70 increases its solubility. Stabilizing the NTD-Hsp70 interaction with small molecules reduces AR aggregation and promotes its degradation in cellular and mouse models of the neuromuscular disorder spinal bulbar muscular atrophy. These results help resolve the mechanisms by which molecular chaperones regulate the balance between AR aggregation, activation and quality control.
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In the absence of androgen ligands, AR protein is bound by protein chaperones such as HSP90 and localized in the cytosol.
“In the absence of androgen ligands, AR protein is bound by protein chaperones such as HSP90 and localized in the cytosol39.”
From Genome-scale CRISPR screens identify PTGES3 as a direct modulator of androgen receptor function in advanced prostate cancer (2025) · cites this paper as [39]
The Results section (‘Hsp70 and Hsp40 bind to the FQNLF motif in cells’; page unavailable) confirms that Hsp40 and Hsp70 bind AR before androgen activation. The Discussion refers to AR concentration in the cytoplasm before androgen binding, but presents that point as part of a proposed model. Our copy does not establish that Hsp90 binds unliganded AR; its Introduction discusses Hsp90 binding to a different receptor, GR. (LLM, conf=0.85)
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References 69 · Cited by 76
- Authors
- Eftekharzadeh, B., Banduseela, V. C., Chiesa, G., Martínez-Cristóbal, P., Rauch, J. N., Nath, S. R., Schwarz, D. M. C., Shao, H., Marin-Argany, M., Di Sanza, C., Giorgetti, E., Yu, Z., Pierattelli, R., Felli, I. C., Brun-Heath, I., García, J., Nebreda, Á. R., Gestwicki, J. E., Lieberman, A. P., & Salvatella, X.
- Affiliations
- Institute for Research in Biomedicine (ES)
- University of Michigan (US)
- University of California, San Francisco (US)
- University of Florence (IT)
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Corresponding author
- Gestwicki, Jason E.
- Lieberman, Andrew P.
- Salvatella, Xavier
- ORCID
- Venue
- Nature Communications
- Published
- 2019-08-08
- Volume
- 10
- Issue
- 1
- Pages
- 3562-3562
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC6687723
- OpenAlex
- W2966912474
- Cited by
- 76
- References
- 69
- Citations by year
- 2026: 5 · 2025: 13 · 2024: 3 · 2023: 17 · 2022: 15 · 2021: 8 · 2020: 14 · 2019: 1
- FWCI
- 3.14
- Type
- journal article
- Language
- en
- Update notices
- correction (2019-10-07)
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Florence Research (University of Florence) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- Institute for Research in Biomedicine
- National Institutes of Health
- Agència de Gestió d'Ajuts Universitaris i de Recerca (BIO2015-70092-R, 2017SGR, BIO2012-31043, 2017 SGR 324)
- National Institute of General Medical Sciences (T32GM007863, T32GM064337, T32GM007315)
- National Institute of Neurological Disorders and Stroke (R01NS055746, R01NS059690)
- H2020 European Research Council (648201)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Keywords
- androgen receptor, HSP70, Hsp40, molecular chaperones, N-terminal domain, ligand-binding domain, receptor activation, protein aggregation, receptor degradation, spinal and bulbar muscular atrophy, transcriptional regulation
- MeSH terms
- Protein Domains, Androgens, Animals, Humans, Ligands, Male, Mice, Transgenic, Receptors, Androgen, Solubility, HSP70 Heat-Shock Proteins, Nuclear Magnetic Resonance, Biomolecular, HSP40 Heat-Shock Proteins, Mice, Protein Multimerization, Gene Knock-In Techniques, HEK293 Cells, Protein Aggregates
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