Prion protein (PrP) synthetic peptides induce cellular PrP to acquire properties of the scrapie isoform
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Date
1995-11
Authors
Kaneko, K.
Peretz, David
Pan, K. K.
Blochberger, Thomas C.
Wille, H.
Gabizon, R.
Griffith, O. H.
Cohen, F. E.
Baldwin, Michael A.
Prusiner, Stanley B.
Journal Title
Journal ISSN
Volume Title
Publisher
Proceedings of the National Academy of Sciences
Abstract
Conversion of the cellular isoform of prion
protein (PrPc) into the scrapie isoform (PrPSc) involves an
increase in the /3-sheet content, diminished solubility, and
resistance to proteolytic digestion. Transgenetic studies argue
that PrPc and PrPSc form a complex during PrPScformation;
thus, synthetic PrP peptides, which mimic the conformational
pluralism of PrP, were mixed with PrPc to determine whether
its properties were altered. Peptides encompassing two a-helical
domains of PrP when mixed with PrPc produced a
complex that displayed many properties of PrPSc. The PrPcpeptide
complex formed fibrous aggregates and up to 65% of
complexed PrPc sedimented at 100,000 x g for 1 h, whereas
PrPc alone did not. These complexes were resistant to pro
teolytic digestion and displayed a high /3-sheet content. Un
expectedly, the peptide in a /3-sheet conformation did not form
the complex, whereas the random coil did. Addition of 2%
Sarkosyl disrupted the complex and rendered PrPc sensitive
to protease digestion. While the pathogenic AllTV mutation
increased the efficacy of complex formation, anti-PrP mono
clonal antibody prevented interaction between PrPc and pep
tides. Our findings in concert with transgenetic investigations
argue that PrPc interacts with PrPSc through a domain that
contains the first two putative a-helices. Whether PrPc-peptide
complexes possess prion infectivity as determined by
bioassays remains to be established.
Description
5 pages
Keywords
Citation
Kaneko, K., Peretz, D., Pan, K.-K., Blochberger, T. C., Wille, H., Gabizon, R., Griffith, O. H., Cohen, F. E., Baldwin, M. A., and Prusiner, S. B. (1995) Prion protein (Pr) synthetic peptides induce cellular PrP to acquire properties of the scrapie isoform. Proc. Natl. Acad. Sci. USA, 92, 11160-11164.