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Targeting prion propagation using peptide constructs with signal sequence motifs
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
Stockholm University, Faculty of Science, Department of Neurochemistry.
Stockholm University, Faculty of Science, Department of Neurochemistry.ORCID iD: 0000-0001-6107-0844
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
2014 (English)In: Archives of Biochemistry and Biophysics, ISSN 0003-9861, E-ISSN 1096-0384, Vol. 564, 254-261 p.Article in journal (Refereed) Published
Abstract [en]

Synthetic peptides with sequences derived from the cellular prion protein (PrPc) unprocessed N-terminus are able to counteract the propagation of proteinase K resistant prions (PrPRes, indicating the presence of the prion isoform of the prion protein) in cell cultures (Lofgren et al., 2008). The anti-prion peptides have characteristics like cell penetrating peptides (CPPs) and consist of the prion protein hydrophobic signal sequence followed by a polycationic motif (residues KKRPKP), in mouse PrPc corresponding to residues 1-28. Here we analyze the sequence elements required for the anti-prion effect of KKRPKP-conjugates. Neuronal GT1-1 cells were infected with either prion strain RML or 22L Variable peptide constructs originating from the mPrP(1-28) sequence were analyzed for anti-prion effects, measured as disappearance of proteinase K resistant prions (PrPRes) in the infected cell cultures. We find that even a 5 amino acid N-terminal shortening of the signal peptide abolishes the anti-prion effect. We show that the signal peptide from PrPc can be replaced with the signal peptide from the Neural cell adhesion molecule-1; NCAMl(1-19), with a retained capacity to reduce PrPRes levels. The anti-prion effect is lost if the polycationic N-terminal PrPc-motif is conjugated to any conventional CPP, such as TAT(48-60), transportan-10 or penetratin. We propose a mechanism by which a signal peptide from a secretory or cell surface protein acts to promote the transport of a prion-binding polycationic PrPc-motif to a subcellular location where prion conversion occurs (most likely the Endosome Recycling Compartment), thereby targeting prion propagation.

Place, publisher, year, edition, pages
2014. Vol. 564, 254-261 p.
Keyword [en]
Prion, Signal peptide, Polycationic motif, Cell penetrating peptide
National Category
Biological Sciences Chemical Sciences
URN: urn:nbn:se:su:diva-113118DOI: 10.1016/ 000346222600030OAI: diva2:790256


Available from: 2015-02-23 Created: 2015-01-23 Last updated: 2015-04-21Bibliographically approved

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Langel, ÜloGräslund, Astrid
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Department of Biochemistry and BiophysicsDepartment of Neurochemistry
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