The Aβpeptide contributes to Alzheimer’s disease through various mechanisms,including cell membrane disruption.While the fibrillar structure of Aβ_(1-42) in aqueous medium has been elucidated,its oligomer structure...The Aβpeptide contributes to Alzheimer’s disease through various mechanisms,including cell membrane disruption.While the fibrillar structure of Aβ_(1-42) in aqueous medium has been elucidated,its oligomer structure remains elusive.We have combined Fourier transform infrared(FTIR)spectroscopy,transmission electron microscopy(TEM),solid-state NMR(ssNMR),and molecular dynamics(MD)approaches to achieve a structural model for Aβ_(1-42) octamer in lipid bilayers.FTIR data identify conformational transitions of Aβ_(1-42) to a stableβ-sheet structure.ssNMR analysis allows assignment of 38 out of 42 Aβ_(1-42) residues,with three additional inter-residue contacts to define the tertiary fold.Combined,MD simulations produce a structural model of Aβ_(1-42) octamers in a novel sushi-roll fold of in-register cross-βmotif with a lipid-filled internal cavity.The membrane-embedded structure of Aβ_(1-42) and the mode of peptide-lipid interactions provide a better understanding of Aβneurotoxicity.展开更多
基金S.A.T.is grateful to the Florida Department of Health,Ed and Ethel Moore Alzheimer’s Disease Research Program(grant 21A06)B.M.thanks the support from NSF of China(grant 32171246).
文摘The Aβpeptide contributes to Alzheimer’s disease through various mechanisms,including cell membrane disruption.While the fibrillar structure of Aβ_(1-42) in aqueous medium has been elucidated,its oligomer structure remains elusive.We have combined Fourier transform infrared(FTIR)spectroscopy,transmission electron microscopy(TEM),solid-state NMR(ssNMR),and molecular dynamics(MD)approaches to achieve a structural model for Aβ_(1-42) octamer in lipid bilayers.FTIR data identify conformational transitions of Aβ_(1-42) to a stableβ-sheet structure.ssNMR analysis allows assignment of 38 out of 42 Aβ_(1-42) residues,with three additional inter-residue contacts to define the tertiary fold.Combined,MD simulations produce a structural model of Aβ_(1-42) octamers in a novel sushi-roll fold of in-register cross-βmotif with a lipid-filled internal cavity.The membrane-embedded structure of Aβ_(1-42) and the mode of peptide-lipid interactions provide a better understanding of Aβneurotoxicity.
