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@ARTICLE{Khemtemourian:909156,
      author       = {Khemtemourian, Lucie and Fatafta, Hebah and Davion, Benoit
                      and Lecomte, Sophie and Castano, Sabine and Strodel, Birgit},
      title        = {{S}tructural {D}issection of the {F}irst {E}vents
                      {F}ollowing {M}embrane {B}inding of the {I}slet {A}myloid
                      {P}olypeptide},
      journal      = {Frontiers in molecular biosciences},
      volume       = {9},
      issn         = {2296-889X},
      address      = {Lausanne},
      publisher    = {Frontiers},
      reportid     = {FZJ-2022-03035},
      pages        = {849979},
      year         = {2022},
      abstract     = {The islet amyloid polypeptide (IAPP) is the main
                      constituent of the amyloid fibrils found in the pancreas of
                      type 2 diabetes patients. The aggregation of IAPP is known
                      to cause cell death, where the cell membrane plays a dual
                      role: being a catalyst of IAPP aggregation and being the
                      target of IAPP toxicity. Using ATR-FTIR spectroscopy,
                      transmission electron microscopy, and molecular dynamics
                      simulations we investigate the very first molecular steps
                      following IAPP binding to a lipid membrane. In particular,
                      we assess the combined effects of the charge state of
                      amino-acid residue 18 and the IAPP-membrane interactions on
                      the structures of monomeric and aggregated IAPP. Distinct
                      IAPP-membrane interaction modes for the various IAPP
                      variants are revealed. Membrane binding causes IAPP to fold
                      into an amphipathic α-helix, which in the case of H18K-,
                      and H18R-IAPP readily moves beyond the headgroup region. For
                      all IAPP variants but H18E-IAPP, the membrane-bound helix is
                      an intermediate on the way to amyloid aggregation, while
                      H18E-IAPP remains in a stable helical conformation. The
                      fibrillar aggregates of wild-type IAPP and H18K-IAPP are
                      dominated by an antiparallel β-sheet conformation, while
                      H18R- and H18A-IAPP exhibit both antiparallel and parallel
                      β-sheets as well as amorphous aggregates. Our results
                      emphasize the decisive role of residue 18 for the structure
                      and membrane interaction of IAPP. This residue is thus a
                      good therapeutic target for destabilizing membrane-bound
                      IAPP fibrils to inhibit their toxic actions.},
      cin          = {IBI-7},
      ddc          = {570},
      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       = {35372496},
      UT           = {WOS:000778672400001},
      doi          = {10.3389/fmolb.2022.849979},
      url          = {https://juser.fz-juelich.de/record/909156},
}