Structural Communication between the E. coli Chaperones DnaK and Hsp90.

Matthew P Grindle,John Paul Alao,Andrea N Kravats,Riina Tehver,Ben Carter,Katherine Connors

doi:10.3390/ijms22042200

Matthew P Grindle, John Paul Alao + Show 4 more

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https://doi.org/10.3390/ijms22042200

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Abstract

The 70 kDa and 90 kDa heat shock proteins Hsp70 and Hsp90 are two abundant and highly conserved ATP-dependent molecular chaperones that participate in the maintenance of cellular homeostasis. In Escherichia coli, Hsp90 (Hsp90) and Hsp70 (DnaK) directly interact and collaborate in protein remodeling. Previous work has produced a model of the direct interaction of both chaperones. The locations of the residues involved have been confirmed and the model has been validated. In this study, we investigate the allosteric communication between Hsp90 and DnaK and how the chaperones couple their conformational cycles. Using elastic network models (ENM), normal mode analysis (NMA), and a structural perturbation method (SPM) of asymmetric and symmetric DnaK-Hsp90, we extract biologically relevant vibrations and identify residues involved in allosteric signaling. When one DnaK is bound, the dominant normal modes favor biological motions that orient a substrate protein bound to DnaK within the substrate/client binding site of Hsp90 and release the substrate from the DnaK substrate binding domain. The presence of one DnaK molecule stabilizes the entire Hsp90 protomer to which it is bound. Conversely, the symmetric model of DnaK binding results in steric clashes of DnaK molecules and suggests that the Hsp90 and DnaK chaperone cycles operate independently. Together, this data supports an asymmetric binding of DnaK to Hsp90.

Highlights

Molecular chaperones play an important role in maintaining homeostasis within the cell by participating in processes such as protein folding, protein remodeling, prevention of aggregation, and disaggregation [1,2,3,4,5,6]
The normal modes of Hsp90Ec in the apo conformation were calculated and compared against the ADP bound state of Hsp90Ec, since these modes are considered to contribute to the biological motion of the protein
The movement of Hsp90Ec from the apo to the ADP bound conformation is best described by two dominant modes

Summary

Introduction

Molecular chaperones play an important role in maintaining homeostasis within the cell by participating in processes such as protein folding, protein remodeling, prevention of aggregation, and disaggregation [1,2,3,4,5,6]. Two highly abundant and evolutionary conserved chaperones include Heat Shock Protein 90 (Hsp90) and Heat Shock Protein. 70 (Hsp70) [7,8,9,10,11,12]. They are present from bacteria to man and paralogs exist in multiple cellular locations. Hsp and Hsp often collaborate in protein remodeling and activation of substrate proteins, termed “clients”, [13,14,15] including many regulatory proteins such as kinases, steroid hormone receptors, and transcription factors [9,12,16,17,18,19,20,21,22,23,24].

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