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@ARTICLE{Hasecke:858389,
      author       = {Hasecke, Filip and Miti, Tatiana and Perez, Carlos and
                      Barton, Jeremy and Schölzel, Daniel and Gremer, Lothar and
                      Grüning, Clara S. R. and Matthews, Garrett and Meisl, Georg
                      and Knowles, Tuomas P. J. and Willbold, Dieter and
                      Neudecker, Philipp and Heise, Henrike and Ullah, Ghanim and
                      Hoyer, Wolfgang and Muschol, Martin},
      title        = {{O}rigin of metastable oligomers and their effects on
                      amyloid fibril self-assembly},
      journal      = {Chemical science},
      volume       = {9},
      number       = {27},
      issn         = {2041-6539},
      address      = {Cambridge},
      publisher    = {RSC},
      reportid     = {FZJ-2018-07275},
      pages        = {5937 - 5948},
      year         = {2018},
      abstract     = {Assembly of rigid amyloid fibrils with their characteristic
                      cross-β sheet structure is a molecular signature of
                      numerous neurodegenerative and non-neuropathic disorders.
                      Frequently large populations of small globular amyloid
                      oligomers (gOs) and curvilinear fibrils (CFs) precede the
                      formation of late-stage rigid fibrils (RFs), and have been
                      implicated in amyloid toxicity. Yet our understanding of the
                      origin of these metastable oligomers, their role as
                      on-pathway precursors or off-pathway competitors, and their
                      effects on the self-assembly of amyloid fibrils remains
                      incomplete. Using two unrelated amyloid proteins, amyloid-β
                      and lysozyme, we find that gO/CF formation, analogous to
                      micelle formation by surfactants, is delineated by a
                      “critical oligomer concentration” (COC). Below this COC,
                      fibril assembly replicates the sigmoidal kinetics of
                      nucleated polymerization. Upon crossing the COC, assembly
                      kinetics becomes biphasic with gO/CF formation responsible
                      for the lag-free initial phase, followed by a second upswing
                      dominated by RF nucleation and growth. RF lag periods below
                      the COC, as expected, decrease as a power law in monomer
                      concentration. Surprisingly, the build-up of gO/CFs above
                      the COC causes a progressive increase in RF lag periods. Our
                      results suggest that metastable gO/CFs are off-pathway from
                      RF formation, confined by a condition-dependent COC that is
                      distinct from RF solubility, underlie a transition from
                      sigmoidal to biphasic assembly kinetics and, most
                      importantly, not only compete with RFs for the shared
                      monomeric growth substrate but actively inhibit their
                      nucleation and growth.},
      cin          = {ICS-6},
      ddc          = {540},
      cid          = {I:(DE-Juel1)ICS-6-20110106},
      pnm          = {551 - Functional Macromolecules and Complexes (POF3-551)},
      pid          = {G:(DE-HGF)POF3-551},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:30079208},
      UT           = {WOS:000438391900009},
      doi          = {10.1039/C8SC01479E},
      url          = {https://juser.fz-juelich.de/record/858389},
}