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ACS Nano. 2015 Sep 22;9(9):9070-7. doi: 10.1021/acsnano.5b03175. Epub 2015 Aug 25.

Cell-Membrane-Mimicking Lipid-Coated Nanoparticles Confer Raman Enhancement to Membrane Proteins and Reveal Membrane-Attached Amyloid-β Conformation.

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Department of Chemical Sciences, Tata Institute of Fundamental Research , Homi Bhabha Road, Colaba, Mumbai 400005, India.
TIFR Centre for Interdisciplinary Sciences , 21 Brundavan Colony, Narsinghi, Hyderabad 500075, India.
Department of Chemistry, Lash Miller Laboratories, University of Toronto , Toronto, ON M5S 3H6, Canada.
Department of Physics, Indian Institute of Science , Bengaluru 560012, India.


Identifying the structures of membrane bound proteins is critical to understanding their function in healthy and diseased states. We introduce a surface enhanced Raman spectroscopy technique which can determine the conformation of membrane-bound proteins, at low micromolar concentrations, and also in the presence of a substantial membrane-free fraction. Unlike conventional surface enhanced Raman spectroscopy, our approach does not require immobilization of molecules, as it uses spontaneous binding of proteins to lipid bilayer-encapsulated Ag nanoparticles. We apply this technique to probe membrane-attached oligomers of Amyloid-β40 (Aβ40), whose conformation is keenly sought in the context of Alzheimer's disease. Isotope-shifts in the Raman spectra help us obtain secondary structure information at the level of individual residues. Our results show the presence of a β-turn, flanked by two β-sheet regions. We use solid-state NMR data to confirm the presence of the β-sheets in these regions. In the membrane-attached oligomer, we find a strongly contrasting and near-orthogonal orientation of the backbone H-bonds compared to what is found in the mature, less-toxic Aβ fibrils. Significantly, this allows a "porin" like β-barrel structure, providing a structural basis for proposed mechanisms of Aβ oligomer toxicity.


amyloid beta peptide; lipid SERS; lipid-coated nanoparticles; membrane protein structures; oligomers; solid-state NMR; surface enhanced Raman spectroscopy

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