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Biological and Structural Basis for Aha1 Regulation of Hsp90 ATPase Activity in Maintaining Proteostasis in the Human Disease Cystic Fibrosis
The activator of Hsp90 ATPase 1, Aha1, has been shown to participate in the Hsp90 chaperone cycle by stimulating the low intrinsic ATPase activity of Hsp90. To elucidate the structural basis for ATPase stimulation of human Hsp90 by human Aha1, we have developed novel mass spectrometry approaches tha...
Autores principales: | , , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
Publicado: |
The American Society for Cell Biology
2010
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2836968/ https://www.ncbi.nlm.nih.gov/pubmed/20089831 http://dx.doi.org/10.1091/mbc.E09-12-1017 |
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author | Koulov, Atanas V. LaPointe, Paul Lu, Bingwen Razvi, Abbas Coppinger, Judith Dong, Meng-Qiu Matteson, Jeanne Laister, Rob Arrowsmith, Cheryl Yates, John R. Balch, William E. |
author_facet | Koulov, Atanas V. LaPointe, Paul Lu, Bingwen Razvi, Abbas Coppinger, Judith Dong, Meng-Qiu Matteson, Jeanne Laister, Rob Arrowsmith, Cheryl Yates, John R. Balch, William E. |
author_sort | Koulov, Atanas V. |
collection | PubMed |
description | The activator of Hsp90 ATPase 1, Aha1, has been shown to participate in the Hsp90 chaperone cycle by stimulating the low intrinsic ATPase activity of Hsp90. To elucidate the structural basis for ATPase stimulation of human Hsp90 by human Aha1, we have developed novel mass spectrometry approaches that demonstrate that the N- and C-terminal domains of Aha1 cooperatively bind across the dimer interface of Hsp90 to modulate the ATP hydrolysis cycle and client activity in vivo. Mutations in both the N- and C-terminal domains of Aha1 impair its ability to bind Hsp90 and stimulate its ATPase activity in vitro and impair in vivo the ability of the Hsp90 system to modulate the folding and trafficking of wild-type and variant (ΔF508) cystic fibrosis transmembrane conductance regulator (CFTR) responsible for the inherited disease cystic fibrosis (CF). We now propose a general model for the role of Aha1 in the Hsp90 ATPase cycle in proteostasis whereby Aha1 regulates the dwell time of Hsp90 with client. We suggest that Aha1 activity integrates chaperone function with client folding energetics by modulating ATPase sensitive N-terminal dimer structural transitions, thereby protecting transient folding intermediates in vivo that could contribute to protein misfolding systems disorders such as CF when destabilized. |
format | Text |
id | pubmed-2836968 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | The American Society for Cell Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-28369682010-05-30 Biological and Structural Basis for Aha1 Regulation of Hsp90 ATPase Activity in Maintaining Proteostasis in the Human Disease Cystic Fibrosis Koulov, Atanas V. LaPointe, Paul Lu, Bingwen Razvi, Abbas Coppinger, Judith Dong, Meng-Qiu Matteson, Jeanne Laister, Rob Arrowsmith, Cheryl Yates, John R. Balch, William E. Mol Biol Cell Articles The activator of Hsp90 ATPase 1, Aha1, has been shown to participate in the Hsp90 chaperone cycle by stimulating the low intrinsic ATPase activity of Hsp90. To elucidate the structural basis for ATPase stimulation of human Hsp90 by human Aha1, we have developed novel mass spectrometry approaches that demonstrate that the N- and C-terminal domains of Aha1 cooperatively bind across the dimer interface of Hsp90 to modulate the ATP hydrolysis cycle and client activity in vivo. Mutations in both the N- and C-terminal domains of Aha1 impair its ability to bind Hsp90 and stimulate its ATPase activity in vitro and impair in vivo the ability of the Hsp90 system to modulate the folding and trafficking of wild-type and variant (ΔF508) cystic fibrosis transmembrane conductance regulator (CFTR) responsible for the inherited disease cystic fibrosis (CF). We now propose a general model for the role of Aha1 in the Hsp90 ATPase cycle in proteostasis whereby Aha1 regulates the dwell time of Hsp90 with client. We suggest that Aha1 activity integrates chaperone function with client folding energetics by modulating ATPase sensitive N-terminal dimer structural transitions, thereby protecting transient folding intermediates in vivo that could contribute to protein misfolding systems disorders such as CF when destabilized. The American Society for Cell Biology 2010-03-15 /pmc/articles/PMC2836968/ /pubmed/20089831 http://dx.doi.org/10.1091/mbc.E09-12-1017 Text en © 2010 by The American Society for Cell Biology |
spellingShingle | Articles Koulov, Atanas V. LaPointe, Paul Lu, Bingwen Razvi, Abbas Coppinger, Judith Dong, Meng-Qiu Matteson, Jeanne Laister, Rob Arrowsmith, Cheryl Yates, John R. Balch, William E. Biological and Structural Basis for Aha1 Regulation of Hsp90 ATPase Activity in Maintaining Proteostasis in the Human Disease Cystic Fibrosis |
title | Biological and Structural Basis for Aha1 Regulation of Hsp90 ATPase Activity in Maintaining Proteostasis in the Human Disease Cystic Fibrosis |
title_full | Biological and Structural Basis for Aha1 Regulation of Hsp90 ATPase Activity in Maintaining Proteostasis in the Human Disease Cystic Fibrosis |
title_fullStr | Biological and Structural Basis for Aha1 Regulation of Hsp90 ATPase Activity in Maintaining Proteostasis in the Human Disease Cystic Fibrosis |
title_full_unstemmed | Biological and Structural Basis for Aha1 Regulation of Hsp90 ATPase Activity in Maintaining Proteostasis in the Human Disease Cystic Fibrosis |
title_short | Biological and Structural Basis for Aha1 Regulation of Hsp90 ATPase Activity in Maintaining Proteostasis in the Human Disease Cystic Fibrosis |
title_sort | biological and structural basis for aha1 regulation of hsp90 atpase activity in maintaining proteostasis in the human disease cystic fibrosis |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2836968/ https://www.ncbi.nlm.nih.gov/pubmed/20089831 http://dx.doi.org/10.1091/mbc.E09-12-1017 |
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