Structural basis for aggregate dissolution and refolding by the Mycobacterium tuberculosis CIpB-DnaK bi-chaperone system

The M. tuberculosis (Mtb) CIpB is a protein disaggregase that helps to rejuvenate the bacterial cell. DnaK is a protein foldase that can function alone, but it can also bind to the CIpB hexamer to physically couple protein disaggregation with protein refolding, although the molecular mechanism is not well understood. Here, we report the cryo-EM analysis of the Mtb CIpB-DnaK bi-chaperone in the presence of ATP gamma S and a protein substrate. We observe three CIpB conformations in the presence of DnaK, identify a conserved TGIP loop linking the oligonucleotide/oligosaccharide-binding domain and the nucleotide-binding domain that is important for CIpB function, derive the interface between the regulatory middle domain of the CIpB and the DnaK nucleotide-binding domain, and find that DnaK binding stabilizes, but does not bend or tilt, the CIpB middle domain. We propose a model for the synergistic actions of aggregate dissolution and refolding by the Mtb CIpB-DnaK bi-chaperone system.

Automated summary

This study uses cryo-EM analysis to investigate the Mtb CIpB-DnaK bi-chaperone system in the presence of ATP gamma S and a protein substrate. The authors identified different conformations of CIpB and crucial loops connecting various domains, proposing a model for the synergistic actions of protein disaggregation and refolding by this bi-chaperone system.