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@ARTICLE{Cukkemane:1043477,
      author       = {Cukkemane, Abhishek and Becker, Nina and Kupreichyk,
                      Tatsiana and Heise, Henrike and Willbold, Dieter and
                      Weiergräber, Oliver H.},
      title        = {{T}racing the aggregation pathway of the scaffold protein
                      {DISC}1: {S}tructural implications for chronic mental
                      illnesses},
      journal      = {Journal of structural biology: X},
      volume       = {11},
      issn         = {2590-1524},
      address      = {Amsterdam},
      publisher    = {Elsevier},
      reportid     = {FZJ-2025-02880},
      pages        = {100128 -},
      year         = {2025},
      abstract     = {Disrupted in schizophrenia 1 (DISC1) is a pleiotropic
                      scaffold protein that is postulated to comprise large
                      disordered regions and four distinct structured segments
                      with a high proportion of helical or coiled-coil fold. DISC1
                      associates with over 300 proteins and is associated with
                      several physiological roles ranging from mitosis to cellular
                      differentiation. Yet, the structural features of the protein
                      are poorly characterized. The C-terminal region (C-region,
                      res. 691–836) forms a tetramer and can also aggregate into
                      amyloid-like fibers, potentially linked to schizophrenia and
                      other chronic mental illnesses. Using a combination of
                      biophysical and structural biology applications, we
                      investigate the structural heterogeneity of three mutants of
                      the C-region, viz., the S713E, S704C and L807-frameshift
                      mutants. We provide evidence for the plasticity of the C
                      region; a thin border separates the conformational
                      flexibility of DISC1 required for interaction with a myriad
                      of partners from disruptive aggregation. Snapshots of
                      aggregates and fibrils growing from a nucleus are presented,
                      along with data supporting the role of the minimal
                      fibrillizing element in the C-region, the β-core. This
                      segment also houses a stretch of residues that is critical
                      for the binding of NDEL1 proteins in the mitotic spindle
                      complex and is absent in the non-binding splice variant
                      DISC1Δ22aa. Physiologically, both the splice variant and
                      the fibers represent loss-of-function states that disrupt
                      cellular division. Our findings highlight the need to
                      decipher the structural elements within the DISC1 C-region
                      to comprehend its physiological role and aggregation-related
                      anomalies, and to establish a rationale for drug
                      development.},
      cin          = {IBI-7},
      ddc          = {624},
      cid          = {I:(DE-Juel1)IBI-7-20200312},
      pnm          = {5244 - Information Processing in Neuronal Networks
                      (POF4-524)},
      pid          = {G:(DE-HGF)POF4-5244},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {40503182},
      UT           = {WOS:001501725600001},
      doi          = {10.1016/j.yjsbx.2025.100128},
      url          = {https://juser.fz-juelich.de/record/1043477},
}