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Cell membrane translocation of the N-terminal (1-28) part of the prion protein
Stockholm University, Faculty of Science, Department of Neurochemistry and Neurotoxicology.
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
Stockholm University, Faculty of Science, Department of Neurochemistry and Neurotoxicology.ORCID iD: 0000-0001-8947-6643
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2002 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 299, no 1, 85-90 p.Article in journal (Refereed) Published
Abstract [en]

The N-terminal (1-28) part of the mouse prion protein (PrP) is a cell penetrating peptide, capable of transporting large hydrophilic cargoes through a cell membrane. Confocal fluorescence microscopy shows that it transports the protein avidin (67 kDa) into several cell lines. The (1-28) peptide has a strong tendency for aggregation and P-structure formation, particularly in interaction with negatively charged phospholipid membranes. The findings have implications for how prion proteins with uncleaved signal peptides in the N-termini may enter into cells, which is important for infection. The secondary structure conversion into beta-structure may be relevant as a seed for the conversion into the scrapie (PrPSc) form of the protein and its arnyloidic transformation.

Place, publisher, year, edition, pages
2002. Vol. 299, no 1, 85-90 p.
Keyword [en]
prion protein N-terminus, cell penetrating peptide, aggregation, beta-structure, membrane interaction
National Category
Biochemistry and Molecular Biology
URN: urn:nbn:se:su:diva-23351DOI: 10.1016/S0006-291X(02)02595-0ISI: 000179496700013OAI: diva2:191479
Available from: 2004-09-16 Created: 2004-09-16 Last updated: 2015-04-22Bibliographically approved
In thesis
1. Cell-penetrating peptides in model membrane systems: Interaction, structure induction and membrane effects
Open this publication in new window or tab >>Cell-penetrating peptides in model membrane systems: Interaction, structure induction and membrane effects
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Despite continuing advances in the development of macromolecules, including peptides, proteins, and oligonucleotides, for therapeutic purposes, the successful application of these hydrophilic molecules has so far been hampered by their inability to efficiently traverse the plasma membrane. The discovery of a class of peptides (cell-penetrating peptides, CPPs) with the ability to mediate the non-invasive and efficient import of a whole host of cargoes, both in vitro and in vivo, has provided a new means by which the problem associated with cellular delivery can be circumvented.

A complete understanding of the translocation mechanism(s) of CPPs has so far proven elusive. Initial studies indicated an ATP-independent, non-endocytotic mechanism, dependent on direct peptide-membrane interactions, making it an enticing challenge from a biophysical point of view. To gain an insight into this mechanism, we identified three new CPP sequences, one corresponding to the third helix of the Islet-1 homeodomain, the other two corresponding to the unprocessed N-termini of the mouse and bovine PrPs, denoted mPrPp and bPrPp, respectively. We then investigated the membrane interactions of these peptides, comparing them to two well-characterized CPPs, the Antennapedia homeodomain-derived pAntp, and the chimeric transportan, in a variety of model membrane systems, using several spectroscopic techniques.

Both pAntp and transportan were found to reside in the headgroup region of the bilayer, oriented along the surface (perpendicular to the bilayer normal). However, differences were observed between the peptides – with the homeodomain-derived peptides, pAntp and pIsl, on the one hand, and transportan and the prion-derived peptides on the other – in terms of their membrane interactions, in particular their membrane perturbation effects. These differences suggest that the peptides belong to two classes of CPPs that translocate through different mechanisms. This hypothesis was given further substance by the recent re-evaluation of the translocation mechanism, which led to the conclusion that many peptides, including pAntp, translocate by an energy-dependent, endocytotic mechanism.

Interesting structural behaviour was observed for the homeodomain-derived CPPs, where they readily underwent an α → β structural conversion, depending on experimental conditions. High peptide concentration and/or high negative membrane surface charge was found to promote β-sheet structure. This structural conversion characteristic was shared by the prion-derived peptides, which along with their CPP property and their membrane perturbation effects, may have implications for the infectivity and toxicity associated with prion diseases.

Place, publisher, year, edition, pages
Stockholm: Institutionen för biokemi och biofysik, 2004. 68 p.
National Category
urn:nbn:se:su:diva-247 (URN)91-7265-956-4 (ISBN)
Public defence
2004-10-08, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 12 A, Stockholm, 14:00
Available from: 2004-09-16 Created: 2004-09-16Bibliographically approved

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Hällbrink, MattiasJarvet, JüriEriksson, L. E. GöranLangel, ÜloGräslund, Astrid
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Department of Neurochemistry and NeurotoxicologyDepartment of Biochemistry and Biophysics
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