PMID:23217711
| Citation |
Zhuravleva, A, Clerico, EM and Gierasch, LM (2012) An interdomain energetic tug-of-war creates the allosterically active state in Hsp70 molecular chaperones. Cell 151:1296-307 |
|---|---|
| Abstract |
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. |
| Links |
PubMed PMC3521165 Online version:10.1016/j.cell.2012.11.002 |
| Keywords |
Adenosine Diphosphate/metabolism; Adenosine Triphosphate/metabolism; Allosteric Regulation; Amino Acid Sequence; Catalytic Domain; Escherichia coli/metabolism; Escherichia coli Proteins/chemistry; Escherichia coli Proteins/genetics; Escherichia coli Proteins/metabolism; HSP70 Heat-Shock Proteins/chemistry; HSP70 Heat-Shock Proteins/genetics; HSP70 Heat-Shock Proteins/metabolism; Models, Molecular; Molecular Sequence Data; Mutation; Nuclear Magnetic Resonance, Biomolecular; Protein Conformation; Protein Structure, Tertiary; Sequence Alignment |
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