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  • Hsp70 and Hsp40 inhibit an inter-domain interaction necessary for transcriptional activity in the androgen receptor.

Hsp70 and Hsp40 inhibit an inter-domain interaction necessary for transcriptional activity in the androgen receptor.

Nature communications (2019-08-10)
Bahareh Eftekharzadeh, Varuna C Banduseela, Giulio Chiesa, Paula Martínez-Cristóbal, Jennifer N Rauch, Samir R Nath, Daniel M C Schwarz, Hao Shao, Marta Marin-Argany, Claudio Di Sanza, Elisa Giorgetti, Zhigang Yu, Roberta Pierattelli, Isabella C Felli, Isabelle Brun-Heath, Jesús García, Ángel R Nebreda, Jason E Gestwicki, Andrew P Lieberman, Xavier Salvatella

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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