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Two-step mechanism of J-domain action in driving Hsp70 function

Abstract

J-domain proteins (JDPs), obligatory Hsp70 cochaperones, play critical roles in protein homeostasis. They promote key allosteric transitions that stabilize Hsp70 interaction with substrate polypeptides upon hydrolysis of its bound ATP. Although a recent crystal structure revealed the physical mode of interaction between a J-domain and an Hsp70, the structural and dynamic consequences of J-domain action once bound and how Hsp70s discriminate among its multiple JDP partners remain enigmatic. We combined free energy simulations, biochemical assays and evolutionary analyses to address these issues. Our results indicate that the invariant aspartate of the J-domain perturbs a conserved intramolecular Hsp70 network of contacts that crosses domains. This perturbation leads to destabilization of the domain-domain interface—thereby promoting the allosteric transition that triggers ATP hydrolysis. While this mechanistic step is driven by conserved residues, evolutionarily variable residues are key to initial JDP/Hsp70 recognition—via electrostatic interactions between oppositely charged surfaces. We speculate that these variable residues allow an Hsp70 to discriminate amongst JDP partners, as many of them have coevolved. Together, our data points to a two-step mode of J-domain action, a recognition stage followed by a mechanistic stage.

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Category:
Articles
Type:
artykuły w czasopismach
Published in:
PLoS Computational Biology no. 16,
ISSN: 1553-7358
Language:
English
Publication year:
2020
Bibliographic description:
Tomiczek B., Delewski W., Nierzwicki Ł., Stolarska M., Grochowina I., Schilke B., Dutkiewicz R., Uzarska M., Ciesielski S., Czub J., Craig E., Marszalek J.: Two-step mechanism of J-domain action in driving Hsp70 function// PLoS Computational Biology -Vol. 16,iss. 6 (2020), s.e1007913-
DOI:
Digital Object Identifier (open in new tab) 10.1371/journal.pcbi.1007913
Verified by:
Gdańsk University of Technology

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