Biological and Structural Basis for Aha1 Regulation of Hsp90 ATPase Activity in Maintaining Proteostasis in the Human Disease Cystic Fibrosis
| Autor: | Paul LaPointe, William E. Balch, John R. Yates, Rob C. Laister, Jeanne Matteson, Judith A. Coppinger, Abbas Razvi, Bingwen Lu, Meng-Qiu Dong, Atanas V. Koulov, Cheryl H. Arrowsmith |
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| Rok vydání: | 2010 |
| Předmět: |
Models
Molecular Protein Folding Cystic Fibrosis Protein Conformation ATPase Molecular Sequence Data Cystic Fibrosis Transmembrane Conductance Regulator Mass Spectrometry 03 medical and health sciences Adenosine Triphosphate 0302 clinical medicine Humans Amino Acid Sequence HSP90 Heat-Shock Proteins ΔF508 Molecular Biology 030304 developmental biology 0303 health sciences biology Activator (genetics) Articles Cell Biology Hsp90 Cystic fibrosis transmembrane conductance regulator Cell biology Proteostasis Cell Biology of Disease Chaperone (protein) Mutation biology.protein Protein folding Protein Multimerization Sequence Alignment 030217 neurology & neurosurgery Molecular Chaperones |
| Zdroj: | Molecular Biology of the Cell |
| ISSN: | 1939-4586 1059-1524 |
| DOI: | 10.1091/mbc.e09-12-1017 |
| Popis: | We propose a general model for the role of the Hsp90 ATPase cycle in proteostasis in which Aha1 regulates the dwell time of Hsp90 with client by integrating chaperone function and client folding energetics by modulating ATPase sensitive N-terminal dimer structural transitions. 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. |
| Databáze: | OpenAIRE |
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