Structural Properties and Dynamic Behavior of Nonfibrillar Oligomers Formed by PrP(106−126)

摘要

Abstract: The formation of nonfibrillar oligomers has been proposed as a common element of thenaggregation pathway of proteins and peptides associated with neurodegenerative diseases such asnAlzheimer’s and Creutzfeldt Jakob disease. While fibrillar structures have long been considered indicatorsnof diseases linked with the accumulation of amyloid plaques, it has more recently been proposed thatnamyloid oligomers are in fact the cytotoxic form. Here we describe the local structure and dynamics ofnstable oligomers formed by a peptide comprising residues 106 126 of the human prion protein (PrP).nStructural constraints from solid-state NMR reveal quaternary packing interactions within the hydrophobicncore, similar to those previously reported for amyloid fibrils formed by this peptide, and consistent withnstructural studies of oligomers formed by the Alzheimer’s u0001-amyloid peptide. However, a hydration-dependentnincrease in disorder is observed for nonfibrillar oligomers of PrP(106 126). In solution NMR spectra wenobserve narrow 1H and 13C resonances corresponding to a monomer in exchange with the ∼30 nm diameternnonfibrillar oligomers, giving additional information on the molecular structure of these species. Takenntogether, our data support a model in which the local structure of the oligomers contains the basic elementsnof amyloid fibrils, but with long-range disorder and local mobility that distinguishes these assemblies fromnthe fibrillar form of PrP(106 126). These characteristics may provide a basis for the differing biologicalnactivities of amyloid fibrils and oligomers.