Dissociation of Recombinant Prion Protein Fibrils into Short Protofilaments: Implications for the Endocytic Pathway and Involvement of the N-Terminal Domain

Fibril dissociation is necessary for efficient conversion of normal prion protein to its misfolded state and continued propagation into amyloid. Recent studies have revealed that conversion occurs along the endocytic pathway. To improve our understanding of the dissociation process, we have investig...

Full description

Saved in:
Bibliographic Details
Published in:Biochemistry (Easton) 2012-06, Vol.51 (22), p.4600-4608
Main Authors: Qi, Xu, Moore, Roger A, McGuirl, Michele A
Format: Article
Language:English
Subjects:
Amyloid - chemistry
Amyloid - metabolism
Amyloid - ultrastructure
Animals
Circular Dichroism
Cricetinae
Endocytosis
Hydrogen-Ion Concentration
Mesocricetus
Prions - chemistry
Prions - metabolism
Prions - ultrastructure
Protein Stability
Protein Structure, Secondary
Protein Structure, Tertiary
Recombinant Proteins - chemistry
Recombinant Proteins - metabolism
Solubility
Spectroscopy, Fourier Transform Infrared
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Fibril dissociation is necessary for efficient conversion of normal prion protein to its misfolded state and continued propagation into amyloid. Recent studies have revealed that conversion occurs along the endocytic pathway. To improve our understanding of the dissociation process, we have investigated the effect of low pH on the stability of recombinant prion fibrils. We show that under conditions that mimic the endocytic environment, amyloid fibrils made from full-length prion protein dissociate both laterally and axially to form protofilaments. Approximately 5% of the protofilaments are short enough to be considered soluble and contain ∼100–300 monomers per structure; these also retain the biophysical characteristics of the filaments. We propose that protonation of His residues and charge repulsion in the N-terminal domain trigger fibril dissociation. Our data suggest that lysosomes and late endosomes are competent milieus for propagating the misfolded state not only by destabilizing the normal prion protein but also by accelerating the dissociation of fibrils into smaller structures that may act as seeds.
ISSN:0006-2960
1520-4995
DOI:10.1021/bi300201e