Molecular chaperones are crucial for maintaining proteostasis in living systems. The bacterial chaperone DnaK, a homologue of heat shock protein (Hsp70), actively holds or unfolds thermosensitive proteins and prevents their misfolding and aggregation [1a]. The DnaK ATPase cycle is stimulated synergistically by two essential co-chaperones, DnaJ and GrpE. The co-chaperone GrpE, a thermosensor, plays a central role as a nucleotide exchange factor and stimulates substrate release from DnaK. GrpE experiences significant structural changes during thermal stress that alter its interaction with DnaK and regulate the chaperone cycle [1b]. Interestingly, bacterial GrpE shows low evolutionary conservation among prokaryotes and eukaryotes, making GrpE an attractive antibacterial target [1c].
We have identified two structural features of E. coli GrpE responsible for regulating its structural stability and influencing its interaction with DnaK. We have shown that introducing hydrophobic functionalities in a stutter of the coiled-coil domain of GrpE homodimer enhances its interaction with DnaK. However, in vivo data suggests that the enhanced binding between GrpE and DnaK was detrimental to the protein folding cycle [2a]. The second structural feature investigated in this study was an edge-to-face aromatic interaction in the highly stable four-helix bundle region of the GrpE homodimer. Replacing the aromatic core with hydrophobic residues disrupted the edge-to-face orientation, resulting in decreased thermosensing activity, leading to heat-sensitive mutants [2b]. In summary, our study suggests that co-chaperone GrpE requires an optimal balance between structural stability and flexibility to perform its co-chaperone function. Our findings demonstrate two essential sites in the co-chaperone GrpE, which could be potential small molecule accessible sites to be explored as prospective antibacterial targets for inhibiting DnaK-GrpE interaction.

Investigations into structural aspects of E. coli co-chaperone GrpE in regulating DnaK function: A potential antibacterial target

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27th CRSI National Symposium in Chemistry

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