NR ATFP
AU Daggett,V.
TI Mapping the early steps in conversion of the prion protein
QU International Conference - Prion 2005: Between fundamentals and society's needs - 19.10.-21.10.2005, Congress Center Düsseldorf - Oral sessions ORAL-20
PT Konferenz-Vortrag
AB Under certain conditions, the prion protein undergoes a conformational change from the normal cellular isoform, PrPc, to PrPsc, an infectious isoform capable of causing neurodegenerative diseases in many mammals. Conversion can be triggered by low pH and in vivo it appears to take place in an endocytic pathway and/or caveolae-like domains. It has thus far been impossible to characterize the conformational change at high resolution using experimental methods. Therefore, to investigate the effect of acidic pH on PrP conformation, we have performed molecular dynamics simulations of PrPc in water at neutral and low pH. The core of the protein is well maintained at neutral pH. At low pH, however, the protein is more dynamic, and the sheet-like structure increases both by lengthening of the native ß-sheet and by addition of a portion of the N-terminus to widen the sheet by another two strands. The 'converted' form is consistent with experimental data available regarding the conversion. These converted forms are being used as building blocks to model the infectious protofibrils and we have identified a novel structure associated with amyloidogenic intermediates.
AD V.Daggett, Department of Medicinal Chemistry, University of Washington, Seattle, USA
SP englisch
PO Deutschland