COVID-19 Response: Local Logistics     National Effort

Development of the structural core and of conformational heterogeneity during the conversion of oligomers of the mouse prion protein to worm-like amyloid fibrils.

You are here

COVID-19 Response: Local Logistics     National Effort

TitleDevelopment of the structural core and of conformational heterogeneity during the conversion of oligomers of the mouse prion protein to worm-like amyloid fibrils.
Publication TypeJournal Article
Year of Publication2012
AuthorsSingh J, Sabareesan AT, Mathew MK, Udgaonkar JB
JournalJ Mol Biol
Volume423
Issue2
Pagination217-31
Date Published2012 Oct 19
ISSN1089-8638
KeywordsAmino Acid Sequence, Amyloid, Animals, Deuterium Exchange Measurement, Kinetics, Mice, Models, Molecular, Molecular Sequence Data, Prion Proteins, Prions, Protein Conformation, Protein Folding
Abstract

Understanding how structure develops during the course of amyloid fibril formation by the prion protein is important for understanding prion diseases. Determining how conformational heterogeneity manifests itself in the fibrillar and pre-fibrillar amyloid aggregates is critical for understanding prion strain phenotypes. In this study, the formation of worm-like amyloid fibrils by the mouse prion protein has been characterized structurally by hydrogen-deuterium exchange coupled to mass spectrometry. The structural cores of these fibrils and of the oligomer on the direct pathway of amyloid fibril formation have been defined, showing how structure develops during fibril formation. The structural core of the oligomer not on the direct pathway has also been defined, allowing the delineation of the structural features that make this off-pathway oligomer incompetent to directly form fibrils. Sequence segments that exhibit multiple local conformations in the three amyloid aggregates have been identified, and the development of structural heterogeneity during fibril formation has been characterized. It is shown that conformational heterogeneity is not restricted to only the C-terminal domain region, which forms the structural core of the aggregates; it manifests itself in the N-terminal domain of the protein as well. Importantly, all three amyloid aggregates are shown to be capable of disrupting lipid membrane structure, pointing to a mechanism by which they may be toxic.

DOI10.1016/j.jmb.2012.06.040
Alternate JournalJ. Mol. Biol.
PubMed ID22789566