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@ARTICLE{Schulz:1021671,
      author       = {Schulz, Celina M. and Pfitzer, Anne and Hoyer, Wolfgang},
      title        = {{F}ibril core regions in engineered α-synuclein dimer are
                      crucial for blocking of fibril elongation},
      journal      = {BBA advances},
      volume       = {4},
      issn         = {2667-1603},
      address      = {[Amsterdam]},
      publisher    = {Elsevier},
      reportid     = {FZJ-2024-00926},
      pages        = {100110 -},
      year         = {2023},
      abstract     = {Synucleinopathies like Parkinson's disease are
                      neurodegenerative diseases which are associated with the
                      deposition of fibrillar aggregates of the endogenous protein
                      α-synuclein (α-syn). The inhibition of the elongation of
                      α-syn fibrils is of great scientific interest and an option
                      in the design of therapeutic strategies. Previously, we
                      developed a disulfide-containing mutant of α-syn, called
                      CC48, which inhibits fibril elongation by blocking of fibril
                      ends. Surprisingly, wildtype (WT) α-syn molecules supported
                      the blocked state, and a fusion of CC48 with WT α-syn,
                      denoted WT-CC48, exhibited increased inhibitory potential.
                      Here, we studied which regions of WT-CC48 are responsible
                      for the strong inhibitory effect. To this end, we
                      investigated a set of truncated versions of WT-CC48 by
                      kinetic elongation assays, density gradient centrifugation,
                      and atomic force microscopy. We show that in both the WT and
                      the CC48 part of the fusion construct the hairpin region
                      (residue 32-60) and NAC region (61-95), but not N- and
                      C-terminal regions, are required for strong inhibition of
                      fibril elongation. The required regions correspond to the
                      segments forming the β-sheet core of α-syn fibrils. As
                      α-syn fibrils typically consist of two protofilaments, the
                      dimeric construct WT-CC48 provides the critical regions
                      sufficient to cover the full β-sheetcore interface exposed
                      at the fibril end, which can explain its high inhibitory
                      efficiency. We suggest a mechanistic model of CC48-mediated
                      inhibition of fibril elongation in which CC48 and WT α-syn
                      cooperatively form an oligomer-like cap at the amyloid
                      fibril end.},
      cin          = {IBI-7},
      ddc          = {610},
      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},
      UT           = {WOS:001223475500003},
      doi          = {10.1016/j.bbadva.2023.100110},
      url          = {https://juser.fz-juelich.de/record/1021671},
}