Abstract
Pseudomonas aeruginosa is an opportunistic pathogen that contributes to the mortality of immunocompromised individuals and patients with cystic fibrosis. Pseudomonas infection presents clinical challenges due to its ability to form biofilms and modulate host-pathogen interactions through the secretion of virulence factors. The calcium-regulated alkaline protease (AP), a member of the repeats in toxin (RTX) family of proteins, is implicated in multiple modes of infection. A series of full-length and truncation mutants were purified for structural and functional studies to evaluate the role of Ca(2+) in AP folding and activation. We find that Ca(2+) binding induces RTX folding, which serves to chaperone the folding of the protease domain. Subsequent association of the RTX domain with an N-terminal α-helix stabilizes AP. These results provide a basis for the Ca(2+)-mediated regulation of AP and suggest mechanisms by which Ca(2+) regulates the RTX family of virulence factors.
Highlights
Pseudomonas aeruginosa alkaline protease is a virulence factor from the repeats in toxin (RTX) family
We find that Ca2؉ binding induces RTX folding, which serves to chaperone the folding of the protease domain
Subsequent association of the RTX domain with an N-terminal ␣-helix stabilizes alkaline protease (AP). These results provide a basis for the Ca2؉mediated regulation of AP and suggest mechanisms by which Ca2؉ regulates the RTX family of virulence factors
Summary
Pseudomonas aeruginosa alkaline protease is a virulence factor from the repeats in toxin (RTX) family. Results: Calcium binding in the RTX domain induces folding and results in activation of the protease. Conclusion: Disorder-to-order transitions in the RTX domain regulate protease structure, stability, and activity. Significance: Understanding how calcium binding regulates the RTX family provides a basis for understanding its impact on bacterial virulence. The calcium-regulated alkaline protease (AP), a member of the repeats in toxin (RTX) family of proteins, is implicated in multiple modes of infection. Subsequent association of the RTX domain with an N-terminal ␣-helix stabilizes AP. These results provide a basis for the Ca2؉mediated regulation of AP and suggest mechanisms by which Ca2؉ regulates the RTX family of virulence factors
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