biostudies-literatureEftekharzadeh BEuropean Research CouncilNINDS NIH HHSNIGMS NIH HHS3562https://www.ebi.ac.uk/biostudies/studies/S-EPMC6687723biostudies-literatureUnknown10(1)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.Nature communicationsHsp70 and Hsp40 inhibit an inter-domain interaction necessary for transcriptional activity in the androgen receptor.PMC6687723T32 GM064337648201T32 GM007863R01 NS055746T32 GM007315R01 NS059690Lieberman APBanduseela VCShao HEftekharzadeh BDi Sanza CFelli ICBrun-Heath IMartinez-Cristobal PNath SRGarcia JPierattelli RSchwarz DMCGestwicki JESalvatella XMarin-Argany MNebreda ARGiorgetti EYu ZChiesa GRauch JNfalseHsp70 and Hsp40 inhibit an inter-domain interaction necessary for transcriptional activity in the androgen receptor.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.2019-01-01T00:00:00Z2019 Aug2024-11-21T03:26:56.736Z2019-08-16T07:02:20ZS-EPMC66877233139588610.1038/s41467-019-11594-y