Conformational equilibria in allosteric control of Hsp70 chaperones
Abstract
Heat-shock proteins of 70 kDa (Hsp70s) are vital for all of life, notably important in protein folding. Hsp70s use ATP binding and hydrolysis at a nucleotide-binding domain (NBD) to control the binding and release of client polypeptides at a substrate-binding domain (SBD); however, the mechanistic basis for this allostery has been elusive. Here, we first characterize biochemical properties of selected domain-interface mutants in bacterial Hsp70 DnaK. We then develop a theoretical model for allosteric equilibria among Hsp70 conformational states to explain the observations: a restraining state, Hsp70R-ATP, restricts ATP hydrolysis and binds peptides poorly; whereas a stimulating state, Hsp70S-ATP, hydrolyzes ATP rapidly and has high intrinsic substrate affinity but rapid binding kinetics. Finally, we support this model for allosteric regulation with DnaK structures obtained in the postulated stimulating state S, with biochemical tests of the S-state interface, and with improved peptide-binding-site definition in an R-state structure.
- Authors:
- Publication Date:
- Research Org.:
- Brookhaven National Lab. (BNL), Upton, NY (United States)
- Sponsoring Org.:
- USDOE; National Institutes of Health (NIH); American Heart Association; Virginia Commonwealth University
- OSTI Identifier:
- 1891365
- Alternate Identifier(s):
- OSTI ID: 1822850; OSTI ID: 1868837
- Report Number(s):
- BNL-222181-2021-JAAM
Journal ID: ISSN 1097-2765; S1097276521006237; PII: S1097276521006237
- Grant/Contract Number:
- P30 GM124165; P41 GM103403; SC0012704; R01GM107462; R01GM098592; R21AI140006; 17GRNT33660506
- Resource Type:
- Published Article
- Journal Name:
- Molecular Cell
- Additional Journal Information:
- Journal Name: Molecular Cell Journal Volume: 81 Journal Issue: 19; Journal ID: ISSN 1097-2765
- Publisher:
- Elsevier
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; allosteric; regulation; crystal; structure; DnaK; Hsp70; molecular; chaperoneprotein; folding
Citation Formats
Wang, Wei, Liu, Qinglian, Liu, Qun, and Hendrickson, Wayne A. Conformational equilibria in allosteric control of Hsp70 chaperones. United States: N. p., 2021.
Web. doi:10.1016/j.molcel.2021.07.039.
Wang, Wei, Liu, Qinglian, Liu, Qun, & Hendrickson, Wayne A. Conformational equilibria in allosteric control of Hsp70 chaperones. United States. https://doi.org/10.1016/j.molcel.2021.07.039
Wang, Wei, Liu, Qinglian, Liu, Qun, and Hendrickson, Wayne A. Fri .
"Conformational equilibria in allosteric control of Hsp70 chaperones". United States. https://doi.org/10.1016/j.molcel.2021.07.039.
@article{osti_1891365,
title = {Conformational equilibria in allosteric control of Hsp70 chaperones},
author = {Wang, Wei and Liu, Qinglian and Liu, Qun and Hendrickson, Wayne A.},
abstractNote = {Heat-shock proteins of 70 kDa (Hsp70s) are vital for all of life, notably important in protein folding. Hsp70s use ATP binding and hydrolysis at a nucleotide-binding domain (NBD) to control the binding and release of client polypeptides at a substrate-binding domain (SBD); however, the mechanistic basis for this allostery has been elusive. Here, we first characterize biochemical properties of selected domain-interface mutants in bacterial Hsp70 DnaK. We then develop a theoretical model for allosteric equilibria among Hsp70 conformational states to explain the observations: a restraining state, Hsp70R-ATP, restricts ATP hydrolysis and binds peptides poorly; whereas a stimulating state, Hsp70S-ATP, hydrolyzes ATP rapidly and has high intrinsic substrate affinity but rapid binding kinetics. Finally, we support this model for allosteric regulation with DnaK structures obtained in the postulated stimulating state S, with biochemical tests of the S-state interface, and with improved peptide-binding-site definition in an R-state structure.},
doi = {10.1016/j.molcel.2021.07.039},
journal = {Molecular Cell},
number = 19,
volume = 81,
place = {United States},
year = {Fri Oct 01 00:00:00 EDT 2021},
month = {Fri Oct 01 00:00:00 EDT 2021}
}
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