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: 3.23). 10/2009; 4(10):e7358. DOI: 10.1371/journal.pone.0007358
Source: PubMed


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,
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    • "How could the N-terminal tail of PrP C modulate so many different activities? One possible model is provided by studies showing that polybasic stretches in the N-terminus of PrP C may penetrate lipid bilayers, functioning as protein transduction domains (Pasupuleti et al., 2009; Wadia et al., 2008). Under specific circumstances , these regions could promote the transient insertion of the N-terminus of PrP C into the plasma membrane, allowing the protein to enter in contact with the cytoplasmic compartment (Fig. 1A). "
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    ABSTRACT: The cellular prion protein (PrP(C)), a cell surface glycoprotein involved in prion disorders, has been shown to mediate the toxicity of several pathological aggregates, including its own misfolded state and some oligomeric assemblies of the amyloid β peptide, which are thought to be primarily responsible for the synaptic dysfunction characterizing Alzheimer's disease. Thus, elucidating the physiological function of PrP(C), and how it could be corrupted by the interaction with misfolded proteins, may provide important insights to understand the pathological processes of prion and Alzheimer's diseases, and possibly other neurodegenerative disorders. In this manuscript, we review the data supporting a role for PrP(C) at the intersection of different neurodegenerative diseases, discuss potential mechanisms by which this protein could mediate neurotoxic signals, and examine therapeutic approaches that may arise from the identification of PrP(C)-directed compounds. Copyright © 2014. Published by Elsevier B.V.
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    • "In accord with this, PrP has antiviral properties and reduces HIV expression [24]. PrP also displays wider antimicrobial activities [25] that are most consistent with innate immune anti-infective functions. "
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    • "Recent studies have demonstrated that the N-terminal polybasic domain (residues 23–31) is essential for the neurotoxicity, ion channel activity, and drug-sensitizing capability of ΔCR PrP and other N-terminally deleted PrP mutants [14], [28]. This region has also been shown to function as a protein transduction domain capable of ferrying polypeptides across the plasma membrane [29], [30]. We hypothesize that residues 23–31 contribute to the cis-activity of ΔCR PrP by allowing the polypeptide to insert into the plasma membrane and form a pore (Figure 11A). "
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