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EMBO Mol Med. 2015 Mar;7(3):339-56. doi: 10.15252/emmm.201404588.

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

Author information

1
Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, AB, Canada Department of Medicine, University of Alberta, Edmonton, AB, 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.
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.
6
CFIA Lab, Nepean, ON, Canada.
7
Tanz Centre for Research in Neurodegenerative Diseases, Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, 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 david.westaway@ualberta.ca.

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)

KEYWORDS:

C2; copper; endoproteolysis; octarepeats; prion

PMID:
25661904
PMCID:
PMC4364950
DOI:
10.15252/emmm.201404588
[Indexed for MEDLINE]
Free PMC Article

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