Document Detail


An interdomain energetic tug-of-war creates the allosterically active state in Hsp70 molecular chaperones.
MedLine Citation:
PMID:  23217711     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The allosteric mechanism of Hsp70 molecular chaperones enables ATP binding to the N-terminal nucleotide-binding domain (NBD) to alter substrate affinity to the C-terminal substrate-binding domain (SBD) and substrate binding to enhance ATP hydrolysis. Cycling between ATP-bound and ADP/substrate-bound states requires Hsp70s to visit a state with high ATPase activity and fast on/off kinetics of substrate binding. We have trapped this "allosterically active" state for the E. coli Hsp70, DnaK, and identified how interactions among the NBD, the β subdomain of the SBD, the SBD α-helical lid, and the conserved hydrophobic interdomain linker enable allosteric signal transmission between ligand-binding sites. Allostery in Hsp70s results from an energetic tug-of-war between domain conformations and formation of two orthogonal interfaces: between the NBD and SBD, and between the helical lid and the β subdomain of the SBD. The resulting energetic tension underlies Hsp70 functional properties and enables them to be modulated by ligands and cochaperones and "tuned" through evolution.
Authors:
Anastasia Zhuravleva; Eugenia M Clerico; Lila M Gierasch
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Cell     Volume:  151     ISSN:  1097-4172     ISO Abbreviation:  Cell     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-12-10     Completed Date:  2013-02-06     Revised Date:  2013-12-12    
Medline Journal Info:
Nlm Unique ID:  0413066     Medline TA:  Cell     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1296-307     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Elsevier Inc. All rights reserved.
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MeSH Terms
Descriptor/Qualifier:
Adenosine Diphosphate / metabolism
Adenosine Triphosphate / metabolism
Allosteric Regulation
Amino Acid Sequence
Catalytic Domain
Escherichia coli / metabolism*
Escherichia coli Proteins / chemistry*,  genetics,  metabolism*
HSP70 Heat-Shock Proteins / chemistry*,  genetics,  metabolism*
Models, Molecular
Molecular Sequence Data
Mutation
Nuclear Magnetic Resonance, Biomolecular
Protein Conformation
Protein Structure, Tertiary
Sequence Alignment
Grant Support
ID/Acronym/Agency:
GM027616/GM/NIGMS NIH HHS; R01 GM027616/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Escherichia coli Proteins; 0/HSP70 Heat-Shock Proteins; 61D2G4IYVH/Adenosine Diphosphate; 8L70Q75FXE/Adenosine Triphosphate; EC 3.6.1.-/dnaK protein, E coli
Comments/Corrections

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