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

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 Sanza, Elisa Giorgetti, Zhigang Yu, Roberta Pierattelli, Isabella C. Felli, Isabelle Brun-Heath, Jesús García, Ángel R. Nebreda, Jason E. Gestwicki (), Andrew P. Lieberman () and Xavier Salvatella ()
Additional contact information
Bahareh Eftekharzadeh: The Barcelona Institute of Science and Technology
Varuna C. Banduseela: University of Michigan
Giulio Chiesa: The Barcelona Institute of Science and Technology
Paula Martínez-Cristóbal: The Barcelona Institute of Science and Technology
Jennifer N. Rauch: University of California at San Francisco, Department of Pharmaceutical Chemistry
Samir R. Nath: University of Michigan
Daniel M. C. Schwarz: University of California at San Francisco, Department of Pharmaceutical Chemistry
Hao Shao: University of California at San Francisco, Department of Pharmaceutical Chemistry
Marta Marin-Argany: The Barcelona Institute of Science and Technology
Claudio Sanza: The Barcelona Institute of Science and Technology
Elisa Giorgetti: University of Michigan
Zhigang Yu: University of Michigan
Roberta Pierattelli: University of Florence
Isabella C. Felli: University of Florence
Isabelle Brun-Heath: The Barcelona Institute of Science and Technology
Jesús García: The Barcelona Institute of Science and Technology
Ángel R. Nebreda: The Barcelona Institute of Science and Technology
Jason E. Gestwicki: University of California at San Francisco, Department of Pharmaceutical Chemistry
Andrew P. Lieberman: University of Michigan
Xavier Salvatella: The Barcelona Institute of Science and Technology

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-11594-y

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