title: Octarepeat region flexibility impacts prion function, endoproteolysis and disease manifestation.
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.
authors: Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, AB, Canada Department of Medicine, University of Alberta, Edmonton, AB, Canada.
authors: Agnes
authors: A
authors: Lau
authors: Department of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, CA, USA.
authors: Alex
authors: A
authors: McDonald
authors: Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, AB, Canada.
authors: Nathalie
authors: N
authors: Daude
authors: Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, AB, Canada.
authors: Charles E
authors: CE
authors: Mays
authors: Department of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, CA, USA.
authors: Eric D
authors: ED
authors: Walter
authors: Department of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, CA, USA.
authors: Robin
authors: R
authors: Aglietti
authors: Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, AB, Canada.
authors: Robert C C
authors: RC
authors: Mercer
authors: Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, AB, Canada.
authors: Serene
authors: S
authors: Wohlgemuth
authors: Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, AB, Canada.
authors: Jacques
authors: J
authors: van der Merwe
authors: Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, AB, Canada.
authors: Jing
authors: J
authors: Yang
authors: Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, AB, Canada.
authors: Hristina
authors: H
authors: Gapeshina
authors: National Prion Disease Surveillance Center, Departments of Pathology and Neurology, School of Medicine Case Western Reserve University, Cleveland, OH, USA.
authors: Chae
authors: C
authors: Kim
authors: Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, AB, Canada.
authors: Jennifer
authors: J
authors: Grams
authors: Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, AB, Canada.
authors: Beipei
authors: B
authors: Shi
authors: Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, AB, Canada Department of Biochemistry, University of Alberta, Edmonton, AB, Canada.
authors: Holger
authors: H
authors: Wille
authors: CFIA Lab, Nepean, ON, Canada.
authors: Aru
authors: A
authors: Balachandran
authors: Tanz Centre for Research in Neurodegenerative Diseases, Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
authors: Gerold
authors: G
authors: Schmitt-Ulms
authors: National Prion Disease Surveillance Center, Departments of Pathology and Neurology, School of Medicine Case Western Reserve University, Cleveland, OH, USA.
authors: Jiri G
authors: JG
authors: Safar
authors: Department of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, CA, USA.
authors: Glenn L
authors: GL
authors: Millhauser
authors: 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.
authors: David
authors: D
authors: Westaway
mesh_terms: D000818:Animals; D002460:Cell Line; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D006651:Histocytochemistry; D006801:Humans; D008822:Mice, Transgenic; D008853:Microscopy; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D018621:PrPC Proteins / Q000737:chemistry* / Q000378:metabolism*; D017096:Prion Diseases / Q000473:pathology* / Q000503:physiopathology*; D011487:Protein Conformation; D011499:Protein Processing, Post-Translational; D059748:Proteolysis
chemical_list: D050505:Mutant Proteins; D018621:PrPC Proteins
keywords: C2; copper; endoproteolysis; octarepeats; prion