SOLUTION STRUCTURE OF OLIGOMERIC PRION PROTEIN FOLDING INTERMEDIATES

Illinois Institute Of Technology, Chicago IL

Investigators

Linked publications, trials & patents

Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Prions are infectious proteins that can adopt two relatively stable structures, and are responsible for Creutzfelt-Jacob disease in humans and BSE ("mad cow") disease in cattle. Although the tendency of prions to form large fibrillar aggregates is well-known, non-fibrillar assemblies of the mammalian prion have been implicated as important species for infection and cell death;however little is known of their molecular structure. A structural model for smaller oligomers of PrP will allow us to better understand their relationship with PrPSc (the pathogenic form of the protein), and to determine their potential role in the pathogenesis of prion diseases. We have identified sample conditions under which folded Syrian hamster PrP(90-231), containing the F198S mutation associated with some cases of human prion disease, will form stable beta-sheet containing oligomers which exhibit proteinase K resistance similar to that reported for human PrPSc and for amyloid fibrils formed by full length ShaPrP. The SAXS studies underway at BioCAT will contribute to a detailed characterization of the molecular structure and dynamic behaviour of beta-sheet rich oligomers formed during the mis-folding of ShaPrP(90-231)-F198S;these studies will provide insight into the molecular mechanisms underlying some cases of familial prion disease.