Staphylokinase has distinct modes of interaction with antimicrobial peptides, modulating its plasminogen-activation properties

Abstract

Staphylokinase (Sak) is a plasminogen activator protein that is secreted by many Staphylococcus aureus strains. Sak also offers protection by binding and inhibiting specific antimicrobial peptides (AMPs). Here, we evaluate Sak as a more general interaction partner for AMPs. Studies with melittin, mCRAMP, tritrpticin and bovine lactoferricin indicate that the truncation of the first ten residues of Sak (Sak "N10), which occurs in vivo and uncovers important residues in a bulge region, improves its affinity for AMPs. Melittin and mCRAMP have a lower affinity for Sak "N10, and in docking studies, they bind to the N-terminal segment and bulge region of Sak "N10. By comparison, lactoferricin and tritrpticin form moderately high affinity 1:1 complexes with Sak "N10 and their cationic residues form several electrostatic interactions with the protein's α-helix. Overall, our work identifies two distinct AMP binding surfaces on Sak "N10 whose occupation would lead to either inhibition or promotion of its plasminogen activating properties.