Open AccessOctarepeat region flexibility impacts prion function, endoproteolysis and disease manifestation
Author(s) -
Lau Agnes,
McDonald Alex,
Daude Nathalie,
Mays Charles E,
Walter Eric D,
Aglietti Robin,
Mercer Robert CC,
Wohlgemuth Serene,
Merwe Jacques,
Yang Jing,
Gapeshina Hristina,
Kim Chae,
Grams Jennifer,
Shi Beipei,
Wille Holger,
Balachandran Aru,
SchmittUlms Gerold,
Safar Jiri G,
Millhauser Glenn L,
Westaway David
Publication year - 2015
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201404588
Subject(s) - recombinant dna , infectivity , transgene , chemistry , linker , prion protein , biophysics , biology , disease , allele , immunology , biochemistry , medicine , gene , virus , computer science , operating system
The cellular prion protein (Pr P 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 Pr P S c in Creutzfeldt‐Jakob disease. Pr P C β‐endoproteolysis to the C2 fragment allows Pr P 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 Pr P 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 Pr P S c and infectivity can either uncouple or engage to drive the onset of clinical disease.