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De novo designed Hsp70 activator dissolves intracellular condensates

Protein quality control (PQC) is carried out in part by the chaperone Hsp70, in concert with adapters of the J-domain protein (JDP) family. The JDPs, also called Hsp40s, are thought to recruit Hsp70 into complexes with specific client proteins. However, the molecular principles regulating this proce...

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Autores principales: Zhang, Jason Z, Greenwood, Nathan, Hernandez, Jason, Cuperus, Josh T, Huang, Buwei, Ryder, Bryan D, Queitsch, Christine, Gestwicki, Jason E, Baker, David
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10541127/
https://www.ncbi.nlm.nih.gov/pubmed/37781598
http://dx.doi.org/10.1101/2023.09.18.558356
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author Zhang, Jason Z
Greenwood, Nathan
Hernandez, Jason
Cuperus, Josh T
Huang, Buwei
Ryder, Bryan D
Queitsch, Christine
Gestwicki, Jason E
Baker, David
author_facet Zhang, Jason Z
Greenwood, Nathan
Hernandez, Jason
Cuperus, Josh T
Huang, Buwei
Ryder, Bryan D
Queitsch, Christine
Gestwicki, Jason E
Baker, David
author_sort Zhang, Jason Z
collection PubMed
description Protein quality control (PQC) is carried out in part by the chaperone Hsp70, in concert with adapters of the J-domain protein (JDP) family. The JDPs, also called Hsp40s, are thought to recruit Hsp70 into complexes with specific client proteins. However, the molecular principles regulating this process are not well understood. We describe the de novo design of a set of Hsp70 binding proteins that either inhibited or stimulated Hsp70’s ATPase activity; a stimulating design promoted the refolding of denatured luciferase in vitro, similar to native JDPs. Targeting of this design to intracellular condensates resulted in their nearly complete dissolution. The designs inform our understanding of chaperone structure-function relationships and provide a general and modular way to target PQC systems to condensates and other cellular targets.
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spelling pubmed-105411272023-10-01 De novo designed Hsp70 activator dissolves intracellular condensates Zhang, Jason Z Greenwood, Nathan Hernandez, Jason Cuperus, Josh T Huang, Buwei Ryder, Bryan D Queitsch, Christine Gestwicki, Jason E Baker, David bioRxiv Article Protein quality control (PQC) is carried out in part by the chaperone Hsp70, in concert with adapters of the J-domain protein (JDP) family. The JDPs, also called Hsp40s, are thought to recruit Hsp70 into complexes with specific client proteins. However, the molecular principles regulating this process are not well understood. We describe the de novo design of a set of Hsp70 binding proteins that either inhibited or stimulated Hsp70’s ATPase activity; a stimulating design promoted the refolding of denatured luciferase in vitro, similar to native JDPs. Targeting of this design to intracellular condensates resulted in their nearly complete dissolution. The designs inform our understanding of chaperone structure-function relationships and provide a general and modular way to target PQC systems to condensates and other cellular targets. Cold Spring Harbor Laboratory 2023-09-19 /pmc/articles/PMC10541127/ /pubmed/37781598 http://dx.doi.org/10.1101/2023.09.18.558356 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
spellingShingle Article
Zhang, Jason Z
Greenwood, Nathan
Hernandez, Jason
Cuperus, Josh T
Huang, Buwei
Ryder, Bryan D
Queitsch, Christine
Gestwicki, Jason E
Baker, David
De novo designed Hsp70 activator dissolves intracellular condensates
title De novo designed Hsp70 activator dissolves intracellular condensates
title_full De novo designed Hsp70 activator dissolves intracellular condensates
title_fullStr De novo designed Hsp70 activator dissolves intracellular condensates
title_full_unstemmed De novo designed Hsp70 activator dissolves intracellular condensates
title_short De novo designed Hsp70 activator dissolves intracellular condensates
title_sort de novo designed hsp70 activator dissolves intracellular condensates
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10541127/
https://www.ncbi.nlm.nih.gov/pubmed/37781598
http://dx.doi.org/10.1101/2023.09.18.558356
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