Cargando…
The Co-Chaperone Hch1 Regulates Hsp90 Function Differently than Its Homologue Aha1 and Confers Sensitivity to Yeast to the Hsp90 Inhibitor NVP-AUY922
Hsp90 is a dimeric ATPase responsible for the activation or maturation of a specific set of substrate proteins termed ‘clients’. This molecular chaperone acts in the context of a structurally dynamic and highly regulated cycle involving ATP, co-chaperone proteins and clients. Co-chaperone proteins r...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2012
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3498168/ https://www.ncbi.nlm.nih.gov/pubmed/23166640 http://dx.doi.org/10.1371/journal.pone.0049322 |
_version_ | 1782249794985525248 |
---|---|
author | Armstrong, Heather Wolmarans, Annemarie Mercier, Rebecca Mai, BaoChan LaPointe, Paul |
author_facet | Armstrong, Heather Wolmarans, Annemarie Mercier, Rebecca Mai, BaoChan LaPointe, Paul |
author_sort | Armstrong, Heather |
collection | PubMed |
description | Hsp90 is a dimeric ATPase responsible for the activation or maturation of a specific set of substrate proteins termed ‘clients’. This molecular chaperone acts in the context of a structurally dynamic and highly regulated cycle involving ATP, co-chaperone proteins and clients. Co-chaperone proteins regulate conformational transitions that may be impaired in mutant forms of Hsp90. We report here that the in vivo impairment of commonly studied Hsp90 variants harbouring the G313S or A587T mutation are exacerbated by the co-chaperone Hch1p. Deletion of HCH1, but not AHA1, mitigates the temperature sensitive phenotype and high sensitivity to Hsp90 inhibitor drugs observed in Saccharomyces cerevisiae that express either of these two Hsp90 variants. Moreover, the deletion of HCH1 results in high resistance to Hsp90 inhibitors in yeast that express wildtype Hsp90. Conversely, the overexpression of Hch1p greatly increases sensitivity to Hsp90 inhibition in yeast expressing wildtype Hsp90. We conclude that despite the similarity between these two co-chaperones, Hch1p and Aha1p regulate Hsp90 function in distinct ways and likely independent of their roles as ATPase stimulators. We further conclude that Hch1p plays a critical role in regulating Hsp90 inhibitor drug sensitivity in yeast. |
format | Online Article Text |
id | pubmed-3498168 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-34981682012-11-19 The Co-Chaperone Hch1 Regulates Hsp90 Function Differently than Its Homologue Aha1 and Confers Sensitivity to Yeast to the Hsp90 Inhibitor NVP-AUY922 Armstrong, Heather Wolmarans, Annemarie Mercier, Rebecca Mai, BaoChan LaPointe, Paul PLoS One Research Article Hsp90 is a dimeric ATPase responsible for the activation or maturation of a specific set of substrate proteins termed ‘clients’. This molecular chaperone acts in the context of a structurally dynamic and highly regulated cycle involving ATP, co-chaperone proteins and clients. Co-chaperone proteins regulate conformational transitions that may be impaired in mutant forms of Hsp90. We report here that the in vivo impairment of commonly studied Hsp90 variants harbouring the G313S or A587T mutation are exacerbated by the co-chaperone Hch1p. Deletion of HCH1, but not AHA1, mitigates the temperature sensitive phenotype and high sensitivity to Hsp90 inhibitor drugs observed in Saccharomyces cerevisiae that express either of these two Hsp90 variants. Moreover, the deletion of HCH1 results in high resistance to Hsp90 inhibitors in yeast that express wildtype Hsp90. Conversely, the overexpression of Hch1p greatly increases sensitivity to Hsp90 inhibition in yeast expressing wildtype Hsp90. We conclude that despite the similarity between these two co-chaperones, Hch1p and Aha1p regulate Hsp90 function in distinct ways and likely independent of their roles as ATPase stimulators. We further conclude that Hch1p plays a critical role in regulating Hsp90 inhibitor drug sensitivity in yeast. Public Library of Science 2012-11-14 /pmc/articles/PMC3498168/ /pubmed/23166640 http://dx.doi.org/10.1371/journal.pone.0049322 Text en © 2012 Armstrong et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Armstrong, Heather Wolmarans, Annemarie Mercier, Rebecca Mai, BaoChan LaPointe, Paul The Co-Chaperone Hch1 Regulates Hsp90 Function Differently than Its Homologue Aha1 and Confers Sensitivity to Yeast to the Hsp90 Inhibitor NVP-AUY922 |
title | The Co-Chaperone Hch1 Regulates Hsp90 Function Differently than Its Homologue Aha1 and Confers Sensitivity to Yeast to the Hsp90 Inhibitor NVP-AUY922 |
title_full | The Co-Chaperone Hch1 Regulates Hsp90 Function Differently than Its Homologue Aha1 and Confers Sensitivity to Yeast to the Hsp90 Inhibitor NVP-AUY922 |
title_fullStr | The Co-Chaperone Hch1 Regulates Hsp90 Function Differently than Its Homologue Aha1 and Confers Sensitivity to Yeast to the Hsp90 Inhibitor NVP-AUY922 |
title_full_unstemmed | The Co-Chaperone Hch1 Regulates Hsp90 Function Differently than Its Homologue Aha1 and Confers Sensitivity to Yeast to the Hsp90 Inhibitor NVP-AUY922 |
title_short | The Co-Chaperone Hch1 Regulates Hsp90 Function Differently than Its Homologue Aha1 and Confers Sensitivity to Yeast to the Hsp90 Inhibitor NVP-AUY922 |
title_sort | co-chaperone hch1 regulates hsp90 function differently than its homologue aha1 and confers sensitivity to yeast to the hsp90 inhibitor nvp-auy922 |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3498168/ https://www.ncbi.nlm.nih.gov/pubmed/23166640 http://dx.doi.org/10.1371/journal.pone.0049322 |
work_keys_str_mv | AT armstrongheather thecochaperonehch1regulateshsp90functiondifferentlythanitshomologueaha1andconferssensitivitytoyeasttothehsp90inhibitornvpauy922 AT wolmaransannemarie thecochaperonehch1regulateshsp90functiondifferentlythanitshomologueaha1andconferssensitivitytoyeasttothehsp90inhibitornvpauy922 AT mercierrebecca thecochaperonehch1regulateshsp90functiondifferentlythanitshomologueaha1andconferssensitivitytoyeasttothehsp90inhibitornvpauy922 AT maibaochan thecochaperonehch1regulateshsp90functiondifferentlythanitshomologueaha1andconferssensitivitytoyeasttothehsp90inhibitornvpauy922 AT lapointepaul thecochaperonehch1regulateshsp90functiondifferentlythanitshomologueaha1andconferssensitivitytoyeasttothehsp90inhibitornvpauy922 AT armstrongheather cochaperonehch1regulateshsp90functiondifferentlythanitshomologueaha1andconferssensitivitytoyeasttothehsp90inhibitornvpauy922 AT wolmaransannemarie cochaperonehch1regulateshsp90functiondifferentlythanitshomologueaha1andconferssensitivitytoyeasttothehsp90inhibitornvpauy922 AT mercierrebecca cochaperonehch1regulateshsp90functiondifferentlythanitshomologueaha1andconferssensitivitytoyeasttothehsp90inhibitornvpauy922 AT maibaochan cochaperonehch1regulateshsp90functiondifferentlythanitshomologueaha1andconferssensitivitytoyeasttothehsp90inhibitornvpauy922 AT lapointepaul cochaperonehch1regulateshsp90functiondifferentlythanitshomologueaha1andconferssensitivitytoyeasttothehsp90inhibitornvpauy922 |