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Antimicrobial Activity of Human Prion Protein Is Mediated by Its N-Terminal Region

Division of Dermatology and Venereology, Department of Clinical Sciences, Lund University, Lund, Sweden.
PLoS ONE (Impact Factor: 3.53). 10/2009; 4(10):e7358. DOI: 10.1371/journal.pone.0007358
Source: PubMed

ABSTRACT 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.
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.
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.

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Available from: Mukesh Pasupulti, Jul 28, 2015
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    • "Recombinant PrP or recombinant PrP23 – 144 , but not PrP90 – 231 , at a concentration of 1 lM displays significant antimicrobial activity against Gram - negative and Gram - positive bacteria ( Pasupuleti et al . 2009 ) . Synthetic pep - tides were used to determine that CC1 is an important feature for this activity . This evidence suggests that NH 2 - PrP C could have immune properties . In support of this hypothesis , PrP C null mice displayed weaker local control of infection in a streptococcal sepsis model ( Ingram et al . 2009 ) ."
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