% IMPORTANT: The following is UTF-8 encoded.  This means that in the presence
% of non-ASCII characters, it will not work with BibTeX 0.99 or older.
% Instead, you should use an up-to-date BibTeX implementation like “bibtex8” or
% “biber”.

@ARTICLE{Maruyama:285051,
      author       = {Maruyama, Riki and Fukumori, Akio and Funamoto, Satoru and
                      Okada, Ken and Akamine, Shoshin and Yanagida, Kanta and
                      Shinohara, Mitsuru and Sato, Naoyuki and Okochi, Masayasu
                      and Kudo, Takashi and Steiner, Harald},
      title        = {γ-{S}ecretase exosites as targets for substrate-selective
                      lowering of {A}β generation.},
      journal      = {Structure},
      volume       = {34},
      number       = {2},
      issn         = {0969-2126},
      address      = {London [u.a.]},
      publisher    = {Elsevier Science},
      reportid     = {DZNE-2026-00175},
      pages        = {363 - 374.e4},
      year         = {2026},
      abstract     = {Intramembrane proteolysis by γ-secretase is critically
                      implicated in Alzheimer disease pathogenesis by processing
                      of its amyloid precursor protein substrate C99 into harmful
                      amyloid-β peptide (Aβ) species. Recruitment of C99
                      involves binding of its N-terminal extracellular domain to
                      exosites in γ-secretase. However, the role of these
                      interactions has been elusive. Here, we show that the
                      N-terminally shorter extracellular domain of the
                      non-amyloidogenic C83 substrate also interacts with
                      γ-secretase exosites, but more weakly. Moreover, we found
                      that bulky aromatic mutations within the 16 amino acid
                      extension of C99 interfere with exosite binding and inhibit
                      substrate cleavage. Likewise, peptides binding to the C99
                      N-terminus that selectively inhibit Aβ production in vitro
                      and in vivo interfere with exosite binding of C99. Our data
                      show that exosite interactions of the C99 N-terminal region
                      with γ-secretase can impact substrate cleavage and indicate
                      that interfering with exosite interactions of C99 may
                      provide a means for modulating amyloidogenic substrate
                      processing.},
      keywords     = {Amyloid Precursor Protein Secretases: metabolism / Amyloid
                      Precursor Protein Secretases: chemistry / Amyloid Precursor
                      Protein Secretases: genetics / Humans / Protein Binding /
                      Amyloid beta-Protein Precursor: metabolism / Amyloid
                      beta-Protein Precursor: chemistry / Amyloid beta-Protein
                      Precursor: genetics / Substrate Specificity / Amyloid
                      beta-Peptides: metabolism / Binding Sites / Proteolysis /
                      Peptide Fragments: metabolism / Peptide Fragments: chemistry
                      / Peptide Fragments: genetics / Models, Molecular / Protein
                      Domains / Mutation / Animals / HEK293 Cells / Alzheimer
                      Disease: metabolism / APP (Other) / Alzheimer's disease
                      (Other) / C83 (Other) / C99 (Other) / amyloid-β peptide
                      (Other) / exosite (Other) / peptide (Other) / γ-secretase
                      (Other) / Amyloid Precursor Protein Secretases (NLM
                      Chemicals) / Amyloid beta-Protein Precursor (NLM Chemicals)
                      / Amyloid beta-Peptides (NLM Chemicals) / Peptide Fragments
                      (NLM Chemicals)},
      cin          = {AG Steiner},
      ddc          = {540},
      cid          = {I:(DE-2719)1110000-1},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:41418776},
      doi          = {10.1016/j.str.2025.11.010},
      url          = {https://pub.dzne.de/record/285051},
}