title: Antimicrobial activity of human prion protein is mediated by its N-terminal region.
abstract: BACKGROUND
  Cellular prion-related protein (PrP(c)) is a cell-surface protein that is ubiquitously expressed in the human body. The multifunctionality of PrP(c), and presence of an exposed cationic and heparin-binding N-terminus, a feature characterizing many antimicrobial peptides, made us hypothesize that PrP(c) could exert antimicrobial activity.
  
  
  RESULTS
  Intact recombinant PrP exerted antibacterial and antifungal effects at normal and low pH. Studies employing recombinant PrP and N- and C-terminally truncated variants, as well as overlapping peptide 20mers, demonstrated that the antimicrobial activity is mediated by the unstructured N-terminal part of the protein. Synthetic peptides of the N-terminus of PrP killed the Gram-negative bacteria Escherichia coli and Pseudomonas aeruginosa, and the Gram-positive Bacillus subtilis and Staphylococcus aureus, as well as the fungus Candida parapsilosis. Fluorescence studies of peptide-treated bacteria, paired with analysis of peptide effects on liposomes, showed that the peptides exerted membrane-breaking effects similar to those seen after treatment with the "classical" human antimicrobial peptide LL-37. In contrast to LL-37, however, no marked helix induction was detected for the PrP-derived peptides in presence of negatively charged (bacteria-mimicking) liposomes. PrP furthermore showed an inducible expression during wounding of human skin ex vivo and in vivo, as well as stimulation of keratinocytes with TGF-alpha in vitro.
  
  
  CONCLUSIONS
  The demonstration of an antimicrobial activity of PrP, localisation of its activity to the N-terminal and heparin-binding region, combined with results showing an increased expression of PrP during wounding, indicate that PrPs could have a previously undisclosed role in host defense.
authors.affiliation: Division of Dermatology and Venereology, Department of Clinical Sciences, Lund University, Lund, Sweden. mukesh.pasupuleti@med.lu.se
authors.forename: Mukesh
authors.initials: M
authors.lastname: Pasupuleti
authors.forename: Markus
authors.initials: M
authors.lastname: Roupe
authors.forename: Victoria
authors.initials: V
authors.lastname: Rydengård
authors.forename: Krystyna
authors.initials: K
authors.lastname: Surewicz
authors.forename: Witold K
authors.initials: WK
authors.lastname: Surewicz
authors.forename: Anna
authors.initials: A
authors.lastname: Chalupka
authors.forename: Martin
authors.initials: M
authors.lastname: Malmsten
authors.forename: Ole E
authors.initials: OE
authors.lastname: Sörensen
authors.forename: Artur
authors.initials: A
authors.lastname: Schmidtchen
mesh_terms: D000890:Anti-Infective Agents / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry / Q000494:pharmacology; D001412:Bacillus subtilis / Q000378:metabolism; D002175:Candida / Q000378:metabolism; D002176:Candida albicans / Q000378:metabolism; D004926:Escherichia coli / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D015603:Keratinocytes / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D011328:Prions / Q000737:chemistry / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011550:Pseudomonas aeruginosa / Q000378:metabolism; D013211:Staphylococcus aureus / Q000378:metabolism; D016211:Transforming Growth Factor alpha / Q000378:metabolism; D054804:Cathelicidins
chemical_list: D000890:Anti-Infective Agents; D023181:Antimicrobial Cationic Peptides; D011328:Prions; D016211:Transforming Growth Factor alpha; D054804:Cathelicidins