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000285051 1001_ $$aMaruyama, Riki$$b0
000285051 245__ $$aγ-Secretase exosites as targets for substrate-selective lowering of Aβ generation.
000285051 260__ $$aLondon [u.a.]$$bElsevier Science$$c2026
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000285051 520__ $$aIntramembrane proteolysis by γ-secretase is critically implicated in Alzheimer disease pathogenesis by processing of its amyloid precursor protein substrate C99 into harmful amyloid-β peptide (Aβ) species. Recruitment of C99 involves binding of its N-terminal extracellular domain to exosites in γ-secretase. However, the role of these interactions has been elusive. Here, we show that the N-terminally shorter extracellular domain of the non-amyloidogenic C83 substrate also interacts with γ-secretase exosites, but more weakly. Moreover, we found that bulky aromatic mutations within the 16 amino acid extension of C99 interfere with exosite binding and inhibit substrate cleavage. Likewise, peptides binding to the C99 N-terminus that selectively inhibit Aβ production in vitro and in vivo interfere with exosite binding of C99. Our data show that exosite interactions of the C99 N-terminal region with γ-secretase can impact substrate cleavage and indicate that interfering with exosite interactions of C99 may provide a means for modulating amyloidogenic substrate processing.
000285051 536__ $$0G:(DE-HGF)POF4-352$$a352 - Disease Mechanisms (POF4-352)$$cPOF4-352$$fPOF IV$$x0
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000285051 650_7 $$2Other$$aAPP
000285051 650_7 $$2Other$$aAlzheimer's disease
000285051 650_7 $$2Other$$aC83
000285051 650_7 $$2Other$$aC99
000285051 650_7 $$2Other$$aamyloid-β peptide
000285051 650_7 $$2Other$$aexosite
000285051 650_7 $$2Other$$apeptide
000285051 650_7 $$2Other$$aγ-secretase
000285051 650_7 $$0EC 3.4.-$$2NLM Chemicals$$aAmyloid Precursor Protein Secretases
000285051 650_7 $$2NLM Chemicals$$aAmyloid beta-Protein Precursor
000285051 650_7 $$2NLM Chemicals$$aAmyloid beta-Peptides
000285051 650_7 $$2NLM Chemicals$$aPeptide Fragments
000285051 650_2 $$2MeSH$$aAmyloid Precursor Protein Secretases: metabolism
000285051 650_2 $$2MeSH$$aAmyloid Precursor Protein Secretases: chemistry
000285051 650_2 $$2MeSH$$aAmyloid Precursor Protein Secretases: genetics
000285051 650_2 $$2MeSH$$aHumans
000285051 650_2 $$2MeSH$$aProtein Binding
000285051 650_2 $$2MeSH$$aAmyloid beta-Protein Precursor: metabolism
000285051 650_2 $$2MeSH$$aAmyloid beta-Protein Precursor: chemistry
000285051 650_2 $$2MeSH$$aAmyloid beta-Protein Precursor: genetics
000285051 650_2 $$2MeSH$$aSubstrate Specificity
000285051 650_2 $$2MeSH$$aAmyloid beta-Peptides: metabolism
000285051 650_2 $$2MeSH$$aBinding Sites
000285051 650_2 $$2MeSH$$aProteolysis
000285051 650_2 $$2MeSH$$aPeptide Fragments: metabolism
000285051 650_2 $$2MeSH$$aPeptide Fragments: chemistry
000285051 650_2 $$2MeSH$$aPeptide Fragments: genetics
000285051 650_2 $$2MeSH$$aModels, Molecular
000285051 650_2 $$2MeSH$$aProtein Domains
000285051 650_2 $$2MeSH$$aMutation
000285051 650_2 $$2MeSH$$aAnimals
000285051 650_2 $$2MeSH$$aHEK293 Cells
000285051 650_2 $$2MeSH$$aAlzheimer Disease: metabolism
000285051 7001_ $$aFukumori, Akio$$b1
000285051 7001_ $$aFunamoto, Satoru$$b2
000285051 7001_ $$aOkada, Ken$$b3
000285051 7001_ $$aAkamine, Shoshin$$b4
000285051 7001_ $$aYanagida, Kanta$$b5
000285051 7001_ $$aShinohara, Mitsuru$$b6
000285051 7001_ $$aSato, Naoyuki$$b7
000285051 7001_ $$aOkochi, Masayasu$$b8
000285051 7001_ $$aKudo, Takashi$$b9
000285051 7001_ $$0P:(DE-2719)2000023$$aSteiner, Harald$$b10$$eLast author$$udzne
000285051 773__ $$0PERI:(DE-600)2031189-8$$a10.1016/j.str.2025.11.010$$gVol. 34, no. 2, p. 363 - 374.e4$$n2$$p363 - 374.e4$$tStructure$$v34$$x0969-2126$$y2026
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