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@ARTICLE{Agerschou:889878,
      author       = {Agerschou, Emil Dandanell and Schützmann, Marie P. and
                      Reppert, Nikolas and Wördehoff, Michael M. and
                      Shaykhalishahi, Hamed and Buell, Alexander K. and Hoyer,
                      Wolfgang},
      title        = {β-{T}urn exchanges in the α-synuclein segment
                      44-{TKEG}-47 reveal high sequence fidelity requirements of
                      amyloid fibril elongation},
      journal      = {Biophysical chemistry},
      volume       = {269},
      issn         = {0301-4622},
      address      = {Amsterdam [u.a.]},
      publisher    = {Elsevier Science},
      reportid     = {FZJ-2021-00486},
      pages        = {106519 -},
      year         = {2021},
      abstract     = {The folding of turns and β-hairpins has been implicated in
                      amyloid formation, with diverse potential consequences such
                      as promotion or inhibition of fibril nucleation, fibril
                      elongation, or off-pathway oligomer formation. In the
                      Parkinson's disease-associated protein α-synuclein (αS), a
                      β-hairpin comprised of residues 36–56 was detected in
                      complex with an engineered binding protein, with a turn
                      formed by the αS sequence segment 44-TKEG-47. Molecular
                      dynamics simulations revealed extensive populations of
                      transient β-hairpin conformations in this region in free,
                      monomeric αS. Here, we investigated potential effects of
                      turn formation on αS fibril formation by studying the
                      aggregation kinetics of an extensive set of αS variants
                      with between two and four amino acid exchanges in the
                      44-TKEG-47 segment. The exchanges were chosen to
                      specifically promote formation of β1-, β1’-, or
                      β2’-turns. All variants assembled into amyloid fibrils,
                      with increased β1’- or β2’-turn propensity associated
                      with faster aggregation and increased β1-turn propensity
                      with slower aggregation compared to wild-type (WT) αS.
                      Atomic force microscopy demonstrated that β-turn exchanges
                      altered fibril morphology. In cross-elongation experiments,
                      the turn variants showed a low ability to elongate WT fibril
                      seeds, and, vice versa, WT monomer did not efficiently
                      elongate turn variant fibril seeds. This demonstrates that
                      sequence identity in the turn region is crucial for
                      efficient αS fibril elongation. Elongation experiments of
                      WT fibril seeds in the presence of both WT and turn variant
                      monomers suggest that the turn variants can bind and block
                      WT fibril ends to different degrees, but cannot efficiently
                      convert into the WT fibril structure. Our results indicate
                      that modifications in the 44-TKEG-47 segment strongly affect
                      amyloid assembly by driving αS into alternative fibril
                      morphologies, whose elongation requires high sequence
                      fidelity.},
      cin          = {IBI-7},
      ddc          = {540},
      cid          = {I:(DE-Juel1)IBI-7-20200312},
      pnm          = {553 - Physical Basis of Diseases (POF3-553) / 5244 -
                      Information Processing in Neuronal Networks (POF4-524) /
                      BETACONTROL - Control of amyloid formation via beta-hairpin
                      molecular recognition features (726368)},
      pid          = {G:(DE-HGF)POF3-553 / G:(DE-HGF)POF4-5244 /
                      G:(EU-Grant)726368},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {33333378},
      UT           = {WOS:000609034700004},
      doi          = {10.1016/j.bpc.2020.106519},
      url          = {https://juser.fz-juelich.de/record/889878},
}