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Abstract:
In Escherichia coli, the binding of non-native protein substrates to the
Hsp70 chaperone DnaK is mediated by the co-chaperone DnaJ. DnaJ
accelerates ATP hydrolysis on DnaK, by closing the peptide-binding cleft
of DnaK. GrpE catalysed nucleotide exchange and ATP re-binding then lead
to substrate release from DnaK, allowing folding. Here we refold
immunoglobulin 27 (I27) to better understand how DnaJ-DnaK-GrpE
chaperones cooperate. When DnaJ is present, I27 is less likely to
misfold and more likely to fold, whereas the unfolded state remains
unaffected. Thus, the 'holdase' DnaJ shows foldase behaviour. Misfolding
of I27 is fully abrogated when DnaJ cooperates with DnaK, which
stabilizes the unfolded state and increases the probability of folding.
Addition of GrpE shifts the unfolded fraction of I27 to pre-chaperone
levels. These insights reveal synergistic mechanisms within the
evolutionary highly conserved Hsp70 system that prevent substrates from
misfolding and promote their productive transition to the native state.
