NR AXVA
AU Redecke,L.; von Bergen,M.; Silvestric,M.; Meyer-Klaucke,W.; Svergun,D.I.; Konarev,P.V.; Georgieva,D.; Genov,N.; Betzel,C.
TI Metal Ion Coordination to Oligomeric Intermediates on the Pathway of Oxidative Prion Protein Aggregation
QU International Conference - Prion 2007 (26.-28.9.2007) Edinburgh International Conference Centre, Edinburgh, Scotland, UK - Book of Abstracts: Protein Misfolding P01.67
IA http://www.prion2007.com/pdf/Prion Book of Abstracts.pdf
PT Konferenz-Poster
AB
Transmissible spongiform encephalopathies (TSE), a group of fatal neurogenerative disorders, are apparently caused by a posttranslational conversion of the cellular prion protein (PrPc) into an abnormal pathological isoform (PrPsc). This process is characterized by dramatic changes in the secondary and tertiary structure of PrP,
resulting in the formation of highly ß-sheeted and insoluble aggregates. Consequently, the enlightenment of the mechanisms of aggregate formation as well as the structural analysis of intermediate oligomeric states will pave the way to understand the molecular principles of prion disease, enabling the design of therapeutic strategies. Taking into account that oxidative stress has been proposed to be a pivotal event in the pathology of TSEs, we investigated the structural changes during PrP aggregation using a novel in vitro conversion assay based on oxidative damage of PrP molecules. It was clearly revealed that oxidation of PrPc is accompanied by fundamental conformational changes resulting in extensive aggregation of highly ß-sheeted PrPisoforms. However, the rate of aggregation differs between species depending on the amount of Met/His residues, which are highly susceptible to oxidation. Moreover, different stable oligomers have been detected on the pathway of aggregation, which were characterized using small angle X-ray scattering (SAXS) techniques. Since increasing evidence suggests that soluble intermediate oligomers may be responsible for cellular neurotoxicity in protein misfolding diseases, these oligomers are interesting candidates. Applying X-ray absorption spectroscopy, we show for the first time that the PrP oligomers retain the ability of monomeric PrPc to coordinate Cu2+ and Zn2+ ions in a specific geometry within the C-terminal domain of the molecule. Identifying the location of the residues involved in metal ion coordination within the PrP aggregates will help to gain deeper insight into the mechanism of PrP conversion and to understand the crucial role of metal ions in neurodegeneration.
AD L. Redecke, M. Silvestric, D. Georgieva, C. Betzel, University of Hamburg, Institute of Biochemistry, Germany; M. von Bergen, Helmholtz Centre for Environmental Research, Department of Proteomics, Germany; W. Meyer-Klaucke, D.I. Svergun, P.V. Konarev, European Molecular Biology Laboratory (EMBL), Germany; N. Genov, Bulgarian Academy of Sciences, Institute of Organic Chemistry, Bulgaria
SP englisch
PO Schottland