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

Henning Leske, Simone Hornemann, Uli Simon Herrmann, Caihong Zhu, Paolo Dametto, Bei Li, Florent Laferriere, Magdalini Polymenidou, Pawel Pelczar, Regina Rose Reimann, Petra Schwarz, Elisabeth Jane Rushing, Kurt Wüthrich, Adriano Aguzzi
PLoS ONE. 2017-02-16; 12(2): e0170503
DOI: 10.1371/journal.pone.0170503

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1. 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.

Leske H(1), Hornemann S(1), Herrmann US(1), Zhu C(1), Dametto P(1), Li B(1),
Laferriere F(2), Polymenidou M(2), Pelczar P(3), Reimann RR(1), Schwarz P(1),
Rushing EJ(1), Wüthrich K(4), Aguzzi A(1).

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.

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.

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

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