Structurally distinct external solvent-exposed domains drive replication of major human prions.
PLoS Pathog
; 17(6): e1009642, 2021 06.
Article
in En
| MEDLINE
| ID: mdl-34138981
ABSTRACT
There is a limited understanding of structural attributes that encode the iatrogenic transmissibility and various phenotypes of prions causing the most common human prion disease, sporadic Creutzfeldt-Jakob disease (sCJD). Here we report the detailed structural differences between major sCJD MM1, MM2, and VV2 prions determined with two complementary synchrotron hydroxyl radical footprinting techniques-mass spectrometry (MS) and conformation dependent immunoassay (CDI) with a panel of Europium-labeled antibodies. Both approaches clearly demonstrate that the phenotypically distant prions differ in a major way with regard to their structural organization, and synchrotron-generated hydroxyl radicals progressively inhibit their seeding potency in a strain and structure-specific manner. Moreover, the seeding rate of sCJD prions is primarily determined by strain-specific structural organization of solvent-exposed external domains of human prion particles that control the seeding activity. Structural characteristics of human prion strains suggest that subtle changes in the organization of surface domains play a critical role as a determinant of human prion infectivity, propagation rate, and targeting of specific brain structures.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Creutzfeldt-Jakob Syndrome
/
PrPSc Proteins
Limits:
Humans
Language:
En
Journal:
PLoS Pathog
Year:
2021
Document type:
Article
Affiliation country:
United States