Article ; Online: Phosphorylation of the Hsp90 Co-Chaperone Hop Changes its Conformational Dynamics and Biological Function.
2022 Volume 435, Issue 3, Page(s) 167931
Abstract: The molecular chaperones Hsp90 and Hsp70 and their regulatory co-chaperone Hop play a key role at the crossroads of the folding pathways of numerous client proteins by forming fine-tuned multiprotein complexes. Alterations of the biomolecules involved ... ...
Abstract | The molecular chaperones Hsp90 and Hsp70 and their regulatory co-chaperone Hop play a key role at the crossroads of the folding pathways of numerous client proteins by forming fine-tuned multiprotein complexes. Alterations of the biomolecules involved may functionally impact the chaperone machinery: here, we integrate simulations and experiments to unveil how Hop conformational fitness and interactions can be controlled by the perturbation of just one residue. Specifically, we unveil how mechanisms mediated by Hop residue Y354 control Hop open and closed states, which affect binding of Hsp70/Hsp90. Phosphorylation or mutation of Hop-Y354 are shown to favor structural ensembles that are indeed not optimal for stable interactions with Hsp90 and Hsp70. This disfavors cellular accumulation of the stringent Hsp90 clients glucocorticoid receptor and the viral tyrosine kinase v-Src, with detrimental effects on v-Src activity. Our results show how the post-translational modification of a specific residue in Hop provides a regulation mechanism for the larger chaperone complex of which it is part. In this framework, the effects of one single alteration are amplified at the cellular level through the perturbation of protein-interaction networks. |
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MeSH term(s) | Humans ; Phosphorylation ; Molecular Chaperones/metabolism ; HSP90 Heat-Shock Proteins/metabolism ; HSP70 Heat-Shock Proteins/metabolism ; Protein-Tyrosine Kinases/metabolism ; Protein Binding | |||||
Chemical Substances | Molecular Chaperones ; HSP90 Heat-Shock Proteins ; HSP70 Heat-Shock Proteins ; Protein-Tyrosine Kinases (EC 2.7.10.1) | |||||
Language | English | |||||
Publishing date | 2022-12-23 | |||||
Publishing country | Netherlands | |||||
Document type | Journal Article ; Research Support, Non-U.S. Gov't | |||||
ZDB-ID | 80229-3 | |||||
ISSN | 1089-8638 ; 0022-2836 | |||||
ISSN (online) | 1089-8638 | |||||
ISSN | 0022-2836 | |||||
DOI | 10.1016/j.jmb.2022.167931 | |||||
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Database | MEDical Literature Analysis and Retrieval System OnLINE |
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