Format

Send to

Choose Destination
PLoS One. 2017 Feb 16;12(2):e0170503. doi: 10.1371/journal.pone.0170503. eCollection 2017.

Protease resistance of infectious prions is suppressed by removal of a single atom in the cellular prion protein.

Author information

1
Institute of Neuropathology, University Hospital of Zurich, University of Zurich, Schmelzbergstrasse 12, Zurich, Switzerland.
2
Institute of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190, Zurich, Switzerland.
3
Institute of Molecular Biology and Biophysics, ETH Zurich, Otto-Stern-Weg 5, Zurich, Switzerland.
4
Department of Integrative Structural and Computational Biology and Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, United States of America.

Abstract

Resistance to proteolytic digestion has long been considered a defining trait of prions in tissues of organisms suffering from transmissible spongiform encephalopathies. Detection of proteinase K-resistant prion protein (PrPSc) still represents the diagnostic gold standard for prion diseases in humans, sheep and cattle. However, it has become increasingly apparent that the accumulation of PrPSc does not always accompany prion infections: high titers of prion infectivity can be reached also in the absence of protease resistant PrPSc. Here, we describe a structural basis for the phenomenon of protease-sensitive prion infectivity. We studied the effect on proteinase K (PK) resistance of the amino acid substitution Y169F, which removes a single oxygen atom from the β2-α2 loop of the cellular prion protein (PrPC). When infected with RML or the 263K strain of prions, transgenic mice lacking wild-type (wt) PrPC but expressing MoPrP169F generated prion infectivity at levels comparable to wt mice. The newly generated MoPrP169F prions were biologically indistinguishable from those recovered from prion-infected wt mice, and elicited similar pathologies in vivo. Surprisingly, MoPrP169F prions showed greatly reduced PK resistance and density gradient analyses showed a significant reduction in high-density aggregates. Passage of MoPrP169F prions into mice expressing wt MoPrP led to full recovery of protease resistance, indicating that no strain shift had taken place. We conclude that a subtle structural variation in the β2-α2 loop of PrPC affects the sensitivity of PrPSc to protease but does not impact prion replication and infectivity. With these findings a specific structural feature of PrPC can be linked to a physicochemical property of the corresponding PrPSc.

PMID:
28207746
PMCID:
PMC5313174
DOI:
10.1371/journal.pone.0170503
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Public Library of Science Icon for PubMed Central
Loading ...
Support Center