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001     285051
005     20260209105900.0
024 7 _ |a 10.1016/j.str.2025.11.010
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024 7 _ |a pmid:41418776
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024 7 _ |a 0969-2126
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024 7 _ |a 1878-4186
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037 _ _ |a DZNE-2026-00175
041 _ _ |a English
082 _ _ |a 540
100 1 _ |a Maruyama, Riki
|b 0
245 _ _ |a γ-Secretase exosites as targets for substrate-selective lowering of Aβ generation.
260 _ _ |a London [u.a.]
|c 2026
|b Elsevier Science
336 7 _ |a article
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336 7 _ |a Journal Article
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336 7 _ |a ARTICLE
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520 _ _ |a 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.
536 _ _ |a 352 - Disease Mechanisms (POF4-352)
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588 _ _ |a Dataset connected to CrossRef, PubMed, , Journals: pub.dzne.de
650 _ 7 |a APP
|2 Other
650 _ 7 |a Alzheimer's disease
|2 Other
650 _ 7 |a C83
|2 Other
650 _ 7 |a C99
|2 Other
650 _ 7 |a amyloid-β peptide
|2 Other
650 _ 7 |a exosite
|2 Other
650 _ 7 |a peptide
|2 Other
650 _ 7 |a γ-secretase
|2 Other
650 _ 7 |a Amyloid Precursor Protein Secretases
|0 EC 3.4.-
|2 NLM Chemicals
650 _ 7 |a Amyloid beta-Protein Precursor
|2 NLM Chemicals
650 _ 7 |a Amyloid beta-Peptides
|2 NLM Chemicals
650 _ 7 |a Peptide Fragments
|2 NLM Chemicals
650 _ 2 |a Amyloid Precursor Protein Secretases: metabolism
|2 MeSH
650 _ 2 |a Amyloid Precursor Protein Secretases: chemistry
|2 MeSH
650 _ 2 |a Amyloid Precursor Protein Secretases: genetics
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Protein Binding
|2 MeSH
650 _ 2 |a Amyloid beta-Protein Precursor: metabolism
|2 MeSH
650 _ 2 |a Amyloid beta-Protein Precursor: chemistry
|2 MeSH
650 _ 2 |a Amyloid beta-Protein Precursor: genetics
|2 MeSH
650 _ 2 |a Substrate Specificity
|2 MeSH
650 _ 2 |a Amyloid beta-Peptides: metabolism
|2 MeSH
650 _ 2 |a Binding Sites
|2 MeSH
650 _ 2 |a Proteolysis
|2 MeSH
650 _ 2 |a Peptide Fragments: metabolism
|2 MeSH
650 _ 2 |a Peptide Fragments: chemistry
|2 MeSH
650 _ 2 |a Peptide Fragments: genetics
|2 MeSH
650 _ 2 |a Models, Molecular
|2 MeSH
650 _ 2 |a Protein Domains
|2 MeSH
650 _ 2 |a Mutation
|2 MeSH
650 _ 2 |a Animals
|2 MeSH
650 _ 2 |a HEK293 Cells
|2 MeSH
650 _ 2 |a Alzheimer Disease: metabolism
|2 MeSH
700 1 _ |a Fukumori, Akio
|b 1
700 1 _ |a Funamoto, Satoru
|b 2
700 1 _ |a Okada, Ken
|b 3
700 1 _ |a Akamine, Shoshin
|b 4
700 1 _ |a Yanagida, Kanta
|b 5
700 1 _ |a Shinohara, Mitsuru
|b 6
700 1 _ |a Sato, Naoyuki
|b 7
700 1 _ |a Okochi, Masayasu
|b 8
700 1 _ |a Kudo, Takashi
|b 9
700 1 _ |a Steiner, Harald
|0 P:(DE-2719)2000023
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773 _ _ |a 10.1016/j.str.2025.11.010
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910 1 _ |a Deutsches Zentrum für Neurodegenerative Erkrankungen
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