Volume 18, Issue 11, Pages (November 2011)

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Volume 18, Issue 11, Pages 1422-1431 (November 2011) Deciphering the Molecular Details for the Binding of the Prion Protein to Main Ganglioside GM1 of Neuronal Membranes  Narinder Sanghera, Bruno E.F.S. Correia, Joana R.S. Correia, Christian Ludwig, Sonya Agarwal, Hironori K. Nakamura, Kazuo Kuwata, Eric Samain, Andrew C. Gill, Boyan B. Bonev, Teresa J.T. Pinheiro  Chemistry & Biology  Volume 18, Issue 11, Pages 1422-1431 (November 2011) DOI: 10.1016/j.chembiol.2011.08.016 Copyright © 2011 Elsevier Ltd Terms and Conditions

Figure 1 Binding of PrP(23–231) to Different Lipids. The blue shift (Δλ) of the fluorescence maximum for PrP(23–231) in the presence of lipid membranes relative to PrP(23–231) in solution (A) Binding of PrP(23–231) to model raft membranes composed of DPPC, cholesterol (chol), and sphingomyelin (SM) (molar ratio of 5:3:2) at pH 5 (open circles) and GM1-enriched rafts containing DPPC/chol/SM/GM1 (molar ratio 10:6:4:5) at pH 7 (triangles), at pH 5 (squares), and in the presence of 200 mM NaCl at pH 5 (filled circles). (B) Binding of PrP(23–231) to single lipid membranes of POPG at pH 5 (circles) and pH 7 (triangles) and POPC at pH 7 (squares). (C) Binding of PrP(23–231) to GM1 micelles at pH 7 (filled circles) and with added 200 mM NaCl at pH 7 (open circles) and pH 5 (triangles). Chemistry & Biology 2011 18, 1422-1431DOI: (10.1016/j.chembiol.2011.08.016) Copyright © 2011 Elsevier Ltd Terms and Conditions

Figure 2 Structural Changes of PrP(23–231) at pH 7.0 (A) Attenuated total reflection Fourier transform infrared and (B) circular dichroism spectra of PrP(23–231) alone (dashed line), with GM1 micelles (continuous line), and with POPG vesicles (dash-dotted line). Chemistry & Biology 2011 18, 1422-1431DOI: (10.1016/j.chembiol.2011.08.016) Copyright © 2011 Elsevier Ltd Terms and Conditions

Figure 3 13C Cross-Polarization/Magic Angle Spinning Solid-State NMR Spectra of Hydrated Lipid Membranes (A) POPC/GM1 (4:1) with PrP(23–231), (B) POPC/GM1 (4:1), and (C) POPC. The molecular structure shows the carbon numbering scheme for GM1 according to Yagi-Utsumi et al. (2010). Chemistry & Biology 2011 18, 1422-1431DOI: (10.1016/j.chembiol.2011.08.016) Copyright © 2011 Elsevier Ltd Terms and Conditions

Figure 4 Enlarged Spectral Regions from the 13C Magic Angle Spinning NMR Spectra The spectra show resonance assignments and highlight changes in spectral intensity and chemical shifts for (A) the carbonyl region, (B) the HC=CH region, (C) the oligosaccharide region, and (D) the hydrocarbon chain and N-acetyl methyl groups for POPC/GM1/PrP(23–231) (top spectrum), POPC/GM1 4:1 (middle spectrum), and POPC (bottom spectrum). Chemistry & Biology 2011 18, 1422-1431DOI: (10.1016/j.chembiol.2011.08.016) Copyright © 2011 Elsevier Ltd Terms and Conditions

Figure 5 Binding of GM1os to PrP (A) Typical quenching spectra of PrP(23–231) with increasing concentrations of GM1os (continuous lines; in the direction of the arrow) compared to PrP(23–231) alone (dashed line). (B) Changes in maximum fluorescence intensity plotted as a function of GM1os concentration for PrP(23–231) (triangles) and PrP(23–110) (circles) at pH 5.0 (filled symbols) and pH 7.0 (open symbols). The data are fitted to a simple two-state model. (C) Circular dichroism spectra of PrP(23–231) alone at pH 5.0 (dashed line) and with increasing concentrations of GM1os (45 μM to 2 mM; black lines). Chemistry & Biology 2011 18, 1422-1431DOI: (10.1016/j.chembiol.2011.08.016) Copyright © 2011 Elsevier Ltd Terms and Conditions

Figure 6 1H-NMR Spectrum of GM1os in Association with PrP(23–231) at pH 5.0 (A) One-dimensional spectrum of GM1os bound to PrP(23–231) in D2O showing all resonances. (B) Saturation transfer difference (STD) NMR spectrum of GM1os bound to PrP(23–231). Protons making close contact with the protein show significant enhancement of their resonances, and the signal intensity is proportional to the strength of binding. (C) Schematic of GM1os with atoms making contact with the protein highlighted. Weak interactions are marked in green, whereas medium and strong interactions are shown in yellow and red, respectively. Protons showing no interactions in the STD-NMR spectrum are unmarked and/or not plotted. Chemistry & Biology 2011 18, 1422-1431DOI: (10.1016/j.chembiol.2011.08.016) Copyright © 2011 Elsevier Ltd Terms and Conditions

Figure 7 Model of the PrP/GM1os complex (A) Ribbon diagram of the structure of the PrP globular domain (green) showing α helices HA, HB, and HC and β sheet strands S1 and S2. The location of the glycosylphosphatidylinositol lipid anchor is highlighted schematically in black. GM1os, shown in stick representation (red), binds to the region between the C-terminal end of helix C and the loop between strand S2 and helix B. (B) Same as (A) but PrP is drawn in surface representation. (C) Same as (B) but the orientation of this panel is a 90° rotation about the vertical axis of (B). (D) The putative binding site of GM1os on PrP. The region colored in orange represents the loop region between strand S2 and helix B, and the region in blue represents the C-terminal end of helix C. The thin red line represents GM1os. All panels are rendered by means of PyMOL (DeLano and Lam, 2005). Chemistry & Biology 2011 18, 1422-1431DOI: (10.1016/j.chembiol.2011.08.016) Copyright © 2011 Elsevier Ltd Terms and Conditions

Chemistry & Biology 2011 18, 1422-1431DOI: (10. 1016/j. chembiol. 2011 Copyright © 2011 Elsevier Ltd Terms and Conditions