Octarepeat region flexibility impacts prion function, endoproteolysis and disease manifestation

EMBO Molecular Medicine

Agnes Lau⁵  Alex McDonald⁴  Nathalie Daude⁵  Charles E Mays⁵  Eric D Walter⁴  Robin Aglietti⁴  Robert CC Mercer⁵  Serene Wohlgemuth⁵  Jacques van der Merwe⁵  Jing Yang⁵  Hristina Gapeshina⁵  Chae Kim³  Jennifer Grams⁵  Beipei Shi⁵  Holger Wille⁵  Aru Balachandran¹  Gerold Schmitt-Ulms²  Jiri G Safar³  Glenn L Millhauser⁴ 

[1] CFIA Lab, Nepean, ON, Canada;Tanz Centre for Research in Neurodegenerative Diseases, Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada;National Prion Disease Surveillance Center, Departments of Pathology and Neurology, School of Medicine, Case Western Reserve University, Cleveland, OH, USA;Department of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, CA, USA;Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, AB, Canada

关键词: C2;    copper;    endoproteolysis;    octarepeats;    prion;   

DOI  :  10.15252/emmm.201404588

来源: Wiley

【 摘 要 】

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^Sc in Creutzfeldt-Jakob disease. PrP^C β-endoproteolysis to the C2 fragment allows PrP^Sc 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^Sc 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^Sc and infectivity can either uncouple or engage to drive the onset of clinical disease.

Synopsis

Flexibility in the N-terminal octarepeat region of the prion protein affects endoproteolysis and disease pathology in transgenic mice. Beyond Creutzfeldt-Jakob disease, the prion mechanism has implications for other misfolding diseases like Alzheimer's or Parkinson's disease.

• β-cleavage of PrP was influenced by the octarepeat region using a mechanism independent from metal-catalysed hydrolysis.
• Modulating the flexibility of the PrP octarepeat region uncoupled PrPSc levels from the onset of disease.
• The octarepeat region acts like a clutch to drive neurological disease.

【 授权许可】

CC BY   
© 2015 The Authors. Published under the terms of the CC BY 4.0 license

Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.