Journal Article

DZNE-2026-00175

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png γ-Secretase exosites as targets for substrate-selective lowering of Aβ generation.

Maruyama, R. ; Fukumori, A. ; Funamoto, S. ; Okada, K. ; Akamine, S. ; Yanagida, K. ; Shinohara, M. ; Sato, N. ; Okochi, M. ; Kudo, T. ; Steiner, H. (Last author)DZNE*

2026
Elsevier Science London [u.a.]

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Please use a persistent id in citations: doi:10.1016/j.str.2025.11.010

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.

Keyword(s): Amyloid Precursor Protein Secretases: metabolism (MeSH) ; Amyloid Precursor Protein Secretases: chemistry (MeSH) ; Amyloid Precursor Protein Secretases: genetics (MeSH) ; Humans (MeSH) ; Protein Binding (MeSH) ; Amyloid beta-Protein Precursor: metabolism (MeSH) ; Amyloid beta-Protein Precursor: chemistry (MeSH) ; Amyloid beta-Protein Precursor: genetics (MeSH) ; Substrate Specificity (MeSH) ; Amyloid beta-Peptides: metabolism (MeSH) ; Binding Sites (MeSH) ; Proteolysis (MeSH) ; Peptide Fragments: metabolism (MeSH) ; Peptide Fragments: chemistry (MeSH) ; Peptide Fragments: genetics (MeSH) ; Models, Molecular (MeSH) ; Protein Domains (MeSH) ; Mutation (MeSH) ; Animals (MeSH) ; HEK293 Cells (MeSH) ; Alzheimer Disease: metabolism (MeSH) ; APP ; Alzheimer's disease ; C83 ; C99 ; amyloid-β peptide ; exosite ; peptide ; γ-secretase ; Amyloid Precursor Protein Secretases ; Amyloid beta-Protein Precursor ; Amyloid beta-Peptides ; Peptide Fragments

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Contributing Institute(s):

1. Biochemistry of γ-Secretase (AG Steiner)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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