Influence of pH on the activity of thrombin-derived antimicrobial peptides.
Biochim Biophys Acta Biomembr
; 1860(11): 2374-2384, 2018 11.
Article
in En
| MEDLINE
| ID: mdl-29885294
ABSTRACT
The wound environment is characterized by physiological pH changes. Proteolysis of thrombin by wound-derived proteases, such as neutrophil elastase, generates antimicrobial thrombin-derived C-terminal peptides (TCPs), such as HVF18 (HVFRLKKWIQKVIDQFGE). Presence of such TCPs in human wound fluids in vivo, as well as the occurrence of an evolutionarily conserved His residue in the primary amino acid sequence of TCPs, prompted us to investigate the pH-dependent antibacterial action of HVF18, as well as of the prototypic GKY25 (GKYGFYTHVFRLKKWIQKVIDQFGE). We show that protonation of this His residue at pHâ¯5.5 increases the antibacterial activity of both TCPs against Gram-negative Escherichia coli by membrane disruption. Physiological salt level (150â¯mM NaCl) augments antibacterial activity of GKY25 but diminishes for the shorter HVF18. Replacing His with Leu or Ser in GKY25 abolishes the His protonation-dependent increase in antibacterial activity at pHâ¯5.5, whereas substitution with Lys maintains activity at neutral (pHâ¯7.4) and acidic pH. Interestingly, both TCPs display decreased binding affinities to human CD14 with decreasing pH, suggesting a likely switch in mode-of-action, from anti-inflammatory at neutral pH to antibacterial at acidic pH. Together, the results demonstrate that apart from structural prerequisites such as peptide length, charge, and hydrophobicity, the evolutionarily conserved His residue of TCPs influences their antibacterial effects and reveals a previously unknown aspect of TCPs biological action.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Thrombin
/
Antimicrobial Cationic Peptides
Limits:
Humans
Language:
En
Journal:
Biochim Biophys Acta Biomembr
Year:
2018
Document type:
Article
Affiliation country:
Singapore