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@ARTICLE{Chen:258782,
      author       = {Chen, Shu-Yu and Feilen, Lukas Peter and
                      Chávez-Gutiérrez, Lucía and Steiner, Harald and
                      Zacharias, Martin},
      title        = {{E}nzyme-substrate hybrid β-sheet controls geometry and
                      water access to the γ-secretase active site.},
      journal      = {Communications biology},
      volume       = {6},
      number       = {1},
      issn         = {2399-3642},
      address      = {London},
      publisher    = {Springer Nature},
      reportid     = {DZNE-2023-00676},
      pages        = {670},
      year         = {2023},
      abstract     = {γ-Secretase is an aspartyl intramembrane protease that
                      cleaves the amyloid precursor protein (APP) involved in
                      Alzheimer's disease pathology and other transmembrane
                      proteins. Substrate-bound structures reveal a stable hybrid
                      β-sheet immediately following the substrate scissile bond
                      consisting of β1 and β2 from the enzyme and β3 from the
                      substrate. Molecular dynamics simulations and enhanced
                      sampling simulations demonstrate that the hybrid β-sheet
                      stability is strongly correlated with the formation of a
                      stable cleavage-compatible active geometry and it also
                      controls water access to the active site. The hybrid
                      β-sheet is only stable for substrates with 3 or more
                      C-terminal residues beyond the scissile bond. The simulation
                      model allowed us to predict the effect of Pro and Phe
                      mutations that weaken the formation of the hybrid β-sheet
                      which were confirmed by experimental testing. Our study
                      provides a direct explanation why γ-secretase
                      preferentially cleaves APP in steps of 3 residues and how
                      the hybrid β-sheet facilitates γ-secretase proteolysis.},
      keywords     = {Amyloid Precursor Protein Secretases: genetics / Amyloid
                      Precursor Protein Secretases: metabolism / Catalytic Domain
                      / Protein Conformation, beta-Strand / Amyloid beta-Protein
                      Precursor: genetics / Amyloid beta-Protein Precursor:
                      metabolism / Water Supply / Amyloid Precursor Protein
                      Secretases (NLM Chemicals) / Amyloid beta-Protein Precursor
                      (NLM Chemicals)},
      cin          = {AG Steiner},
      ddc          = {570},
      cid          = {I:(DE-2719)1110000-1},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pmc          = {pmc:PMC10290658},
      pubmed       = {pmid:37355752},
      doi          = {10.1038/s42003-023-05039-y},
      url          = {https://pub.dzne.de/record/258782},
}