In Situ Molecular-Level Insights into the Interfacial Structure Changes of Membrane-Associated Prion Protein Fragment [118–135] Investigated by Sum Frequency Generation Vibrational Spectroscopy

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Abstract

Protein aggregation is associated with many "protein deposition diseases". A precise molecular detail of the conformational transitions of such a membrane-associated protein structure is critical to understand the disease mechanism and develop effective treatments. One potential model peptide for studying the mechanism of protein deposition diseases is prion protein fragment [118-135] (PrP118-135), which shares homology with the C-terminal domain of the Alzheimer's β-amyloid peptide. In this study, sum frequency generation vibrational spectroscopy (SFG-VS) has been applied to characterize interactions between PrP118-135 and 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-(1'-rac-glycerol) (POPG) lipid bilayer in situ. The conformation change and orientation of PrP118-135 in lipid bilayers have been determined using SFG spectra with different polarization combinations. It is found that low-concentration PrP118-135 predominantly adopts α-helical structure but with tiny β-sheet structure. With the PrP118-135 concentration increasing, the molecular number ratio of parallel β-sheet structure increases and reaches about 44% at a concentration of 0.10 mg/mL, indicating the formation of abnormally folded scrapie isoforms. The α-helical structure inserts into the lipid bilayer with a tilt angle of ~32° versus the surface normal, while the β-sheet structure lies down on the lipid bilayer with the tilt and twist angle both of 90°. The 3300 cm(-1) N-H stretching signal in psp spectra arises from α-helical structure at low PrP concentration and from the β-sheet structure at high PrP concentration. Results from this study will provide an in-depth insight into the early events in the aggregation of PrP in cell membrane.

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