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Octarepeat region flexibility impacts prion function, endoproteolysis and disease manifestation.

Authors
  • Lau, Agnes1
  • McDonald, Alex2
  • Daude, Nathalie3
  • Mays, Charles E3
  • Walter, Eric D2
  • Aglietti, Robin2
  • Mercer, Robert C C3
  • Wohlgemuth, Serene3
  • van der Merwe, Jacques3
  • Yang, Jing3
  • Gapeshina, Hristina3
  • Kim, Chae4
  • Grams, Jennifer3
  • Shi, Beipei3
  • Wille, Holger5
  • Balachandran, Aru6
  • Schmitt-Ulms, Gerold7
  • Safar, Jiri G4
  • Millhauser, Glenn L2
  • Westaway, David8
  • 1 Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, AB, Canada Department of Medicine, University of Alberta, Edmonton, AB, Canada. , (Canada)
  • 2 Department of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, CA, USA.
  • 3 Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, AB, Canada. , (Canada)
  • 4 National Prion Disease Surveillance Center, Departments of Pathology and Neurology, School of Medicine Case Western Reserve University, Cleveland, OH, USA.
  • 5 Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, AB, Canada Department of Biochemistry, University of Alberta, Edmonton, AB, Canada. , (Canada)
  • 6 CFIA Lab, Nepean, ON, Canada. , (Canada)
  • 7 Tanz Centre for Research in Neurodegenerative Diseases, Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada. , (Canada)
  • 8 Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, AB, Canada Department of Medicine, University of Alberta, Edmonton, AB, Canada Department of Biochemistry, University of Alberta, Edmonton, AB, Canada [email protected] , (Canada)
Type
Published Article
Journal
EMBO Molecular Medicine
Publisher
EMBO
Publication Date
March 2015
Volume
7
Issue
3
Pages
339–356
Identifiers
DOI: 10.15252/emmm.201404588
PMID: 25661904
Source
Medline
Keywords
License
Unknown

Abstract

The cellular prion protein (PrP(C)) comprises a natively unstructured N-terminal domain, including a metal-binding octarepeat region (OR) and a linker, followed by a C-terminal domain that misfolds to form PrP(S) (c) in Creutzfeldt-Jakob disease. PrP(C) β-endoproteolysis to the C2 fragment allows PrP(S) (c) formation, while α-endoproteolysis blocks production. To examine the OR, we used structure-directed design to make novel alleles, 'S1' and 'S3', locking this region in extended or compact conformations, respectively. S1 and S3 PrP resembled WT PrP in supporting peripheral nerve myelination. Prion-infected S1 and S3 transgenic mice both accumulated similar low levels of PrP(S) (c) and infectious prion particles, but differed in their clinical presentation. Unexpectedly, S3 PrP overproduced C2 fragment in the brain by a mechanism distinct from metal-catalysed hydrolysis reported previously. OR flexibility is concluded to impact diverse biological endpoints; it is a salient variable in infectious disease paradigms and modulates how the levels of PrP(S) (c) and infectivity can either uncouple or engage to drive the onset of clinical disease.

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