Deciphering the Molecular Details for the Binding of the Prion Protein to Main Ganglioside GM1 of Neuronal Membranes

SummaryThe prion protein (PrP) resides in lipid rafts in vivo, and lipids modulate misfolding of the protein to infectious isoforms. Here we demonstrate that binding of recombinant PrP to model raft membranes requires the presence of ganglioside GM1. A combination of liquid- and solid-state NMR revealed the binding sites of PrP to the saccharide head group of GM1. The binding epitope for GM1 was mapped to the folded C-terminal domain of PrP, and docking simulations identified key residues in the C-terminal region of helix C and the loop between strand S2 and helix B. Crucially, this region of PrP is linked to prion resistance in vivo, and structural changes caused by lipid binding in this region may explain the requirement for lipids in the generation of infectious prions in vitro.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (430 K)Download as PowerPoint slideHighlights► The full-length prion protein binds to GM1 in neuronal rafts ► The atomic details of the binding epitope in the GM1-PrP complex were revealed by NMR ► Binding of PrP to GM1 preserves the α-helical structure of PrP ► The binding site was mapped to the loop region in PrP, a region modulating disease