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

Autor:	Eftekharzadeh B; Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028, Barcelona, Spain.; Joint BSC-IRB Research Programme in Computational Biology, Baldiri Reixac 10, 08028, Barcelona, Spain., Banduseela VC; Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA., Chiesa G; Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028, Barcelona, Spain.; Joint BSC-IRB Research Programme in Computational Biology, Baldiri Reixac 10, 08028, Barcelona, Spain., Martínez-Cristóbal P; Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028, Barcelona, Spain.; Joint BSC-IRB Research Programme in Computational Biology, Baldiri Reixac 10, 08028, Barcelona, Spain., Rauch JN; University of California at San Francisco, Department of Pharmaceutical Chemistry, 675 Nelson Rising Lane, San Francisco, CA, 94158, USA., Nath SR; Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA., Schwarz DMC; University of California at San Francisco, Department of Pharmaceutical Chemistry, 675 Nelson Rising Lane, San Francisco, CA, 94158, USA., Shao H; University of California at San Francisco, Department of Pharmaceutical Chemistry, 675 Nelson Rising Lane, San Francisco, CA, 94158, USA., Marin-Argany M; Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028, Barcelona, Spain.; Joint BSC-IRB Research Programme in Computational Biology, Baldiri Reixac 10, 08028, Barcelona, Spain., Di Sanza C; Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028, Barcelona, Spain.; Joint BSC-IRB Research Programme in Computational Biology, Baldiri Reixac 10, 08028, Barcelona, Spain., Giorgetti E; Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA., Yu Z; Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA., Pierattelli R; CERM and Department of Chemistry 'Ugo Schiff', University of Florence, Via Luigi Sacconi 6, 50019, Sesto Fiorentino, Florence, Italy., Felli IC; CERM and Department of Chemistry 'Ugo Schiff', University of Florence, Via Luigi Sacconi 6, 50019, Sesto Fiorentino, Florence, Italy., Brun-Heath I; Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028, Barcelona, Spain.; Joint BSC-IRB Research Programme in Computational Biology, Baldiri Reixac 10, 08028, Barcelona, Spain., García J; Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028, Barcelona, Spain., Nebreda ÁR; Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028, Barcelona, Spain.; ICREA, Passeig Lluís Companys 23, 08010, Barcelona, Spain., Gestwicki JE; University of California at San Francisco, Department of Pharmaceutical Chemistry, 675 Nelson Rising Lane, San Francisco, CA, 94158, USA. jason.gestwicki@ucsf.edu., Lieberman AP; Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA. liebermn@umich.edu., Salvatella X; Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028, Barcelona, Spain. xavier.salvatella@irbbarcelona.org.; Joint BSC-IRB Research Programme in Computational Biology, Baldiri Reixac 10, 08028, Barcelona, Spain. xavier.salvatella@irbbarcelona.org.; ICREA, Passeig Lluís Companys 23, 08010, Barcelona, Spain. xavier.salvatella@irbbarcelona.org.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2019 Aug 08; Vol. 10 (1), pp. 3562. Date of Electronic Publication: 2019 Aug 08.
DOI:	10.1038/s41467-019-11594-y
Abstrakt:	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.
Databáze:	MEDLINE
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