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@ARTICLE{Cukkemane:905391,
      author       = {Cukkemane, Abhishek Arun and Becker, Nina and Zielinski,
                      Mara and Frieg, Benedikt and Lakomek, Nils-Alexander and
                      Heise, Henrike and Schröder, Gunnar F. and Willbold, Dieter
                      and Weiergräber, Oliver H.},
      title        = {{C}onformational heterogeneity coupled with β-fibril
                      formation of a scaffold protein involved in chronic mental
                      illnesses},
      journal      = {Translational Psychiatry},
      volume       = {11},
      number       = {1},
      issn         = {2158-3188},
      address      = {London},
      publisher    = {Nature Publishing Group},
      reportid     = {FZJ-2022-00643},
      pages        = {639},
      year         = {2021},
      abstract     = {Chronic mental illnesses (CMIs) pose a significant
                      challenge to global health due to their complex and poorly
                      understood etiologies and hence, absence of causal
                      therapies. Research of the past two decades has revealed
                      dysfunction of the disrupted in schizophrenia 1 (DISC1)
                      protein as a predisposing factor involved in several
                      psychiatric disorders. DISC1 is a multifaceted protein that
                      serves myriads of functions in mammalian cells, for
                      instance, influencing neuronal development and synapse
                      maintenance. It serves as a scaffold hub forming complexes
                      with a variety (~300) of partners that constitute its
                      interactome. Herein, using combinations of structural and
                      biophysical tools, we demonstrate that the C-region of the
                      DISC1 protein is highly polymorphic, with important
                      consequences for its physiological role. Results from
                      solid-state NMR spectroscopy and electron microscopy
                      indicate that the protein not only forms symmetric oligomers
                      but also gives rise to fibrils closely resembling those
                      found in certain established amyloid proteinopathies.
                      Furthermore, its aggregation as studied by isothermal
                      titration calorimetry (ITC) is an exergonic process,
                      involving a negative enthalpy change that drives the
                      formation of oligomeric (presumably tetrameric) species as
                      well as β-fibrils. We have been able to narrow down the
                      β-core region participating in fibrillization to residues
                      716–761 of full-length human DISC1. This region is absent
                      in the DISC1Δ22aa splice variant, resulting in reduced
                      association with proteins from the dynein motor complex,
                      viz., NDE-like 1 (NDEL1) and lissencephaly 1 (LIS1), which
                      are crucial during mitosis. By employing surface plasmon
                      resonance, we show that the oligomeric DISC1 C-region has an
                      increased affinity and shows cooperativity in binding to
                      LIS1 and NDEL1, in contrast to the noncooperative binding
                      mode exhibited by the monomeric version. Based on the
                      derived structural models, we propose that the association
                      between the binding partners involves two neighboring
                      subunits of DISC1 C-region oligomers. Altogether, our
                      findings highlight the significance of the DISC1 C-region as
                      a crucial factor governing the balance between its
                      physiological role as a multifunctional scaffold protein and
                      aggregation-related aberrations with potential significance
                      for disease.},
      cin          = {IBI-7},
      ddc          = {610},
      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       = {pmid:34921141},
      UT           = {WOS:000731253800001},
      doi          = {10.1038/s41398-021-01765-1},
      url          = {https://juser.fz-juelich.de/record/905391},
}