Structure and activity of the Lugdulysin M30 zinc metallopeptidase, a potential virulence factor from Staphylococcus lugdunensis

Abstract Staphylococcus lugdunensis, a skin commensal, secretes metallopeptidase Lugdulysin associated with bone-joint infections. We structurally and functionally characterize Lugdulysin. Crystallographic structures of the native protein and of an inactive double mutant reveal the intramolecular chaperone role of the N-term 22 residues of the propeptide in the mature protein. E242Q-Y315F non-active Prolugdulysin structure highlights the presence of the C-term part of the propeptide buried inside the catalytic cleft, defining an aspartate-switch maturation. To become functional, Prolugdulysin is maturated in trans as observed by incubation with Lugdulysins functionally active and not. We determine an overall kcat/Km with synthetic substrates and confirm importance of a hydrophobic residue at -3 and/or +3 position for specific substrate recognition. Moreover, Lugdulysin exhibits a protective effect against bactericidal activity of cathelicidin, strengthening a potential role of virulence factor. These results pave ways to design inhibitory molecules of potential clinical interest.