Native Thrombocidin-1 and Unfolded Thrombocidin-1 Exert Antimicrobial Activity via Distinct Structural Elements

Abstract

Background:The properties required for antimicrobial activity of chemokines are unclear. Results: Native thrombocidin-1 requires a three-dimensional positive patch for activity, but unfolded thrombocidin-1 is active through the N-terminal linear peptide regions. Conclusion: Native thrombocidin-1 and unfolded thrombocidin-1 exert activity via distinct structural elements. Significance: Folded and unfolded antimicrobial chemokines can exert activity through different structural elements.

CXCL14 Displays Antimicrobial Activity against Respiratory Tract Bacteria and Contributes to Clearance of Streptococcus pneumoniae Pulmonary Infection

“…Intact CXCL14, however, is also quite potent in killing Gram-positive species, and this effect was evident in vivo indicating that the tertiary structure of CXCL14 could be responsible for interaction with the cell wall of Gram-positive bacteria. The notion that different mechanisms could be responsible for the killing of Gram-positive and Gram-negative bacteria is consistent with a recent study where N-terminal peptides of thrombocidin-1 were compared with the full-size molecule and found to be less active against Gram-positive S. aureus, but equally efficient with E. coli (26). Accordingly, it is logical to assume that the composition of the linear peptide stretch is important in short peptides where three-dimensional structural elements such as positive patches are less likely to occur.…”

“…This finding was unexpected because positively charged a-helices were considered to be an epitome for a chemokine with AMP function (7,8,24,40). Nevertheless, CXCL6 and thrombocidin-1, a truncated form of CXCL7, are other examples of antimicrobial chemokines where the microbicidal effect is mediated by 50-and 15-aa-long N-terminal peptides, respectively (25,26,46). Moreover, similar to other chemokines and defensins, CXCL14 displayed antimicrobial activity after linearization (7,27,47).…”

“…An initial screening for antimicrobial activity of chemokines revealed that large patches of positive electrostatic charges on the surface is an important characteristic to distinguish antimicrobial from nonantimicrobial chemokines (9), whereas cationic amino acids, which are often clustered in the C-terminal a-helix, are thought to interact with the negatively charged bacterial membranes (7,8,24). However, as described for CXCL6 (25) and for thrombocidin-1, a variant of CXCL7 lacking C-terminal alanine and aspartate (26), there are exceptions where key structural features for antimicrobial activity of chemokines lie in the N-terminal part. It seems that disulfide bonds are not essential for antimicrobial activity of chemokines (7,27,28).…”

Platelets and Their Interactions with Other Immune Cells

“…α granules also contain proteins that exhibit anti-microbial effects and thus influence innate immune function. Examples include thrombocidin 1 and 2, which have anti-bacterial and anti-fungal actions (115). α granules also contain proteins that possess mitogenic and angiogenic abilities and thus regulate wound healing and angiogenesis function.…”

Platelets as Immune Cells in Infectious Diseases

“…Beside tPMP, the thrombocidins TC1 and TC2 also have the potency to inhibit the growth of bacteria in vitro, such as E. coli, Bacillus subtilis and S. aureus [51,114]. The IE model confirmed these results in vivo, demonstrating that TC1 and TC2 are involved in the clearance of Streptococcus viridans from the endocardial surface; bacterial strains with low TC1/TC2 susceptibility could persist on the surface, whereas highly susceptible bacteria were rapidly eliminated [115,116].…”