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

Author

Listed:
  • Bahareh Eftekharzadeh

    (The Barcelona Institute of Science and Technology
    Joint BSC-IRB Research Programme in Computational Biology, Baldiri Reixac 10)

  • Varuna C. Banduseela

    (University of Michigan)

  • Giulio Chiesa

    (The Barcelona Institute of Science and Technology
    Joint BSC-IRB Research Programme in Computational Biology, Baldiri Reixac 10)

  • Paula Martínez-Cristóbal

    (The Barcelona Institute of Science and Technology
    Joint BSC-IRB Research Programme in Computational Biology, Baldiri Reixac 10)

  • 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
    Joint BSC-IRB Research Programme in Computational Biology, Baldiri Reixac 10)

  • Claudio Sanza

    (The Barcelona Institute of Science and Technology
    Joint BSC-IRB Research Programme in Computational Biology, Baldiri Reixac 10)

  • 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
    Joint BSC-IRB Research Programme in Computational Biology, Baldiri Reixac 10)

  • Jesús García

    (The Barcelona Institute of Science and Technology)

  • Ángel R. Nebreda

    (The Barcelona Institute of Science and Technology
    ICREA)

  • 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
    Joint BSC-IRB Research Programme in Computational Biology, Baldiri Reixac 10
    ICREA)

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.

Suggested Citation

  • 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 & Eli, 2019. "Hsp70 and Hsp40 inhibit an inter-domain interaction necessary for transcriptional activity in the androgen receptor," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-11594-y
    DOI: 10.1038/s41467-019-11594-y
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