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

N. Sanghera, B. Correia, J.R.S. Correia, C. Ludwig, S. Agarwal, H.K. Nakamura, K. Kuwata, E. Samain, A.C. Gill, B.B. Bonev, T.J.T. Pinheiro

Research output: Contribution to journalArticlepeer-review

Abstract

The 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.
Original languageEnglish
Pages (from-to)1422-1431
Number of pages10
JournalChemistry and Biology
Volume18
Issue number11
DOIs
Publication statusPublished - 2011

Keywords

  • scrapie-associated form lipid-membranes natural scrapie cells prp fibrillization microdomains aggregation association conversion

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