Hsp70 and Hsp40 inhibit an inter-domain interaction necessary for transcriptional activity in the androgen receptor.
Androgens
/ metabolism
Animals
Gene Knock-In Techniques
HEK293 Cells
HSP40 Heat-Shock Proteins
/ metabolism
HSP70 Heat-Shock Proteins
/ metabolism
Humans
Ligands
Male
Mice
Mice, Transgenic
Nuclear Magnetic Resonance, Biomolecular
Protein Aggregates
Protein Domains
Protein Multimerization
Receptors, Androgen
/ chemistry
Solubility
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
08 08 2019
08 08 2019
Historique:
received:
04
01
2019
accepted:
23
07
2019
entrez:
10
8
2019
pubmed:
10
8
2019
medline:
8
1
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 31395886
doi: 10.1038/s41467-019-11594-y
pii: 10.1038/s41467-019-11594-y
pmc: PMC6687723
doi:
Substances chimiques
AR protein, human
0
Androgens
0
DNAJA2 protein, human
0
HSP40 Heat-Shock Proteins
0
HSP70 Heat-Shock Proteins
0
HSPA1A protein, human
0
Ligands
0
Protein Aggregates
0
Receptors, Androgen
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3562Subventions
Organisme : European Research Council
ID : 648201
Pays : International
Organisme : NINDS NIH HHS
ID : R01 NS059690
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007863
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS055746
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM064337
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007315
Pays : United States
Commentaires et corrections
Type : ErratumIn
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