Structurally distinct external solvent-exposed domains drive replication of major human prions
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Updated: Nov 1, 2025
Protein Misfolding Cyclic Amplification of Prions
Published on: November 7, 2012
Mohammad Khursheed Siddiqi1, Chae Kim1, Tracy Haldiman1
1Department of Pathology, Case Western Reserve University, Cleveland, Ohio, United States of America.
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.
Insights
Structural differences in sporadic Creutzfeldt-Jakob disease (sCJD) prions impact their infectivity and propagation. Understanding these prion structures is key to deciphering disease mechanisms and developing treatments.
Area of Science:
- Neuroscience
- Structural Biology
- Infectious Diseases
Background:
- Sporadic Creutzfeldt-Jakob disease (sCJD) is the most common human prion disease.
- Limited understanding exists regarding structural attributes of prions that determine transmissibility and phenotypes.
Purpose of the Study:
- To determine detailed structural differences between major sCJD prion strains (MM1, MM2, VV2).
- To investigate how structural organization influences prion seeding potency and infectivity.
Main Methods:
- Utilized two complementary synchrotron hydroxyl radical footprinting techniques: mass spectrometry (MS) and conformation-dependent immunoassay (CDI).
- Employed a panel of Europium-labeled antibodies for enhanced detection and characterization.
Main Results:
- Phenotypically distinct sCJD prions (MM1, MM2, VV2) exhibit significant differences in structural organization.
- Synchrotron hydroxyl radicals inhibited prion seeding potency in a strain- and structure-specific manner.
- Prion seeding rate is determined by the structure of solvent-exposed external domains.
Conclusions:
- Subtle changes in the surface domain organization of human prion strains critically determine prion infectivity, propagation rate, and brain targeting.
- Structural characteristics of prions are crucial for understanding sCJD pathogenesis.
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