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@ARTICLE{Khaled:1015354,
      author       = {Khaled, Mohammed and Rönnbäck, Isabel and Ilag, Leopold
                      L. and Gräslund, Astrid and Strodel, Birgit and Österlund,
                      Nicklas},
      title        = {{A} {H}airpin {M}otif in the {A}myloid-β {P}eptide {I}s
                      {I}mportant for {F}ormation of {D}isease-{R}elated
                      {O}ligomers},
      journal      = {Journal of the American Chemical Society},
      volume       = {145},
      number       = {33},
      issn         = {0002-7863},
      address      = {Washington, DC},
      publisher    = {ACS Publications},
      reportid     = {FZJ-2023-03674},
      pages        = {18340 - 18354},
      year         = {2023},
      abstract     = {The amyloid-β (Aβ) peptide is associated with the
                      development of Alzheimer’s disease and is known to form
                      highly neurotoxic prefibrillar oligomeric aggregates, which
                      are difficult to study due to their transient,
                      low-abundance, and heterogeneous nature. To obtain
                      high-resolution information about oligomer structure and
                      dynamics as well as relative populations of assembly states,
                      we here employ a combination of native ion mobility mass
                      spectrometry and molecular dynamics simulations. We find
                      that the formation of Aβ oligomers is dependent on the
                      presence of a specific β-hairpin motif in the peptide
                      sequence. Oligomers initially grow spherically but start to
                      form extended linear aggregates at oligomeric states larger
                      than those of the tetramer. The population of the extended
                      oligomers could be notably increased by introducing an
                      intramolecular disulfide bond, which prearranges the peptide
                      in the hairpin conformation, thereby promoting oligomeric
                      structures but preventing conversion into mature fibrils.
                      Conversely, truncating one of the β-strand-forming segments
                      of Aβ decreased the hairpin propensity of the peptide and
                      thus decreased the oligomer population, removed the
                      formation of extended oligomers entirely, and decreased the
                      aggregation propensity of the peptide. We thus propose that
                      the observed extended oligomer state is related to the
                      formation of an antiparallel sheet state, which then
                      nucleates into the amyloid state. These studies provide
                      increased mechanistic understanding of the earliest steps in
                      Aβ aggregation and suggest that inhibition of Aβ folding
                      into the hairpin conformation could be a viable strategy for
                      reducing the amount of toxic oligomers.},
      cin          = {IBI-7},
      ddc          = {540},
      cid          = {I:(DE-Juel1)IBI-7-20200312},
      pnm          = {5241 - Molecular Information Processing in Cellular Systems
                      (POF4-524)},
      pid          = {G:(DE-HGF)POF4-5241},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {37555670},
      UT           = {WOS:001044984100001},
      doi          = {10.1021/jacs.3c03980},
      url          = {https://juser.fz-juelich.de/record/1015354},
}