Abstract
Copper resistance is a key virulence trait of the uropathogen Proteus mirabilis. Here we show that P. mirabilis ScsC (PmScsC) contributes to this defence mechanism by enabling swarming in the presence of copper. We also demonstrate that PmScsC is a thioredoxin-like disulfide isomerase but, unlike other characterized proteins in this family, it is trimeric. PmScsC trimerization and its active site cysteine are required for wild-type swarming activity in the presence of copper. Moreover, PmScsC exhibits unprecedented motion as a consequence of a shape-shifting motif linking the catalytic and trimerization domains. The linker accesses strand, loop and helical conformations enabling the sampling of an enormous folding landscape by the catalytic domains. Mutation of the shape-shifting motif abolishes disulfide isomerase activity, as does removal of the trimerization domain, showing that both features are essential to foldase function. More broadly, the shape-shifter peptide has the potential for ‘plug and play’ application in protein engineering.
Highlights
Copper resistance is a key virulence trait of the uropathogen Proteus mirabilis
The gene encoding P. mirabilis C2LPE2 is located within a cluster of four predicted suppressor of copper sensitivity (Scs) genes and we proposed this the encoded protein would contribute to bacterial copper resistance
Typhimurium ScsC—not a disulfide isomerase—confer copper resistance? How do the very diverse ScsC proteins form redox relay systems with a predicted partner protein ScsB14 that appears to be highly conserved in bacterial Scs gene clusters? The likely explanation for the diversity in architecture and flexibility of ScsC proteins may relate to differences in their target specificity
Summary
Copper resistance is a key virulence trait of the uropathogen Proteus mirabilis. Here we show that P. mirabilis ScsC (PmScsC) contributes to this defence mechanism by enabling swarming in the presence of copper. We demonstrate that PmScsC is a thioredoxin-like disulfide isomerase but, unlike other characterized proteins in this family, it is trimeric. Mutation of the shape-shifting motif abolishes disulfide isomerase activity, as does removal of the trimerization domain, showing that both features are essential to foldase function. E. coli DsbC is a dimeric V-shaped thioredoxin-fold protein disulfide isomerase[3] that proof-reads and shuffles incorrect disulfide bonds[4]. We find that it is not DsbA-like, as it does not catalyse disulfide bond formation. We show that this thioredoxin fold protein is unlike any other characterized to date—it is trimeric—and we demonstrate that its function depends on a shape-shifting motif that could potentially be used as a ‘plug and play’ peptide module
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