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PEDS Advance Access published online on August 2, 2008
Protein Engineering Design and Selection, doi:10.1093/protein/gzn042
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Novel dominant-negative prion protein mutants identified from a randomized library

David Ott1,3, Cornelia Taraborrelli2,3 and Adriano Aguzzi4

Institute of Neuropathology, University Hospital Zurich, Schmelzbergstrasse 12, CH-8091 Zurich, Switzerland

4 To whom correspondence should be addressed. E-mail: adriano.aguzzi{at}usz.ch

Prion diseases are untreatable neurodegenerative disorders characterized by accumulation of PrPSc, an aggregated isoform of the cellular prion protein (PrPC). We generated a library of PrP variants with random mutations in the helix-3 domain and screened for dominant-negative mutants (DNMs) that would inhibit replication of prions (the Rocky Mountain Laboratory strain) in infected N2a cells. Two of the identified PrP mutants, Q167R and Q218K, were already known to counteract prion replication, thereby validating the effectiveness of this approach. In addition, novel DNMs were found efficiently to antagonize PrPSc propagation in cells. In contrast to Q167R and Q218K, the newly identified DNMs S221P and Y217C resided on the cell surface at a substantially lower level, suggesting that robust cell surface display of DNM might not be a general prerequisite for efficient prion antagonism. The newly identified DNMs point to useful target-selective therapeutic tools for the treatment of prion diseases.

Keywords: dominant-negative mutant/helix 3-library/prion/PrP/screening

Received January 7, 2008; revised June 15, 2008; accepted June 27, 2008.

1 Present address: MorphoSys AG, Lena-Christ-Strasse 48, D-82152 Martinsried/Planegg, Germany

2 Present address: Klinische Immunologie, University Hospital Zürich, Moussonstrasse 13, CH-8044 Zürich, Switzerland

3 These authors contributed equally.


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