TY  - JOUR
AU  - Maruyama, Riki
AU  - Fukumori, Akio
AU  - Funamoto, Satoru
AU  - Okada, Ken
AU  - Akamine, Shoshin
AU  - Yanagida, Kanta
AU  - Shinohara, Mitsuru
AU  - Sato, Naoyuki
AU  - Okochi, Masayasu
AU  - Kudo, Takashi
AU  - Steiner, Harald
TI  - γ-Secretase exosites as targets for substrate-selective lowering of Aβ generation.
JO  - Structure
VL  - 34
IS  - 2
SN  - 0969-2126
CY  - London [u.a.]
PB  - Elsevier Science
M1  - DZNE-2026-00175
SP  - 363 - 374.e4
PY  - 2026
AB  - 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.
KW  - Amyloid Precursor Protein Secretases: metabolism
KW  - Amyloid Precursor Protein Secretases: chemistry
KW  - Amyloid Precursor Protein Secretases: genetics
KW  - Humans
KW  - Protein Binding
KW  - Amyloid beta-Protein Precursor: metabolism
KW  - Amyloid beta-Protein Precursor: chemistry
KW  - Amyloid beta-Protein Precursor: genetics
KW  - Substrate Specificity
KW  - Amyloid beta-Peptides: metabolism
KW  - Binding Sites
KW  - Proteolysis
KW  - Peptide Fragments: metabolism
KW  - Peptide Fragments: chemistry
KW  - Peptide Fragments: genetics
KW  - Models, Molecular
KW  - Protein Domains
KW  - Mutation
KW  - Animals
KW  - HEK293 Cells
KW  - Alzheimer Disease: metabolism
KW  - APP (Other)
KW  - Alzheimer's disease (Other)
KW  - C83 (Other)
KW  - C99 (Other)
KW  - amyloid-β peptide (Other)
KW  - exosite (Other)
KW  - peptide (Other)
KW  - γ-secretase (Other)
KW  - Amyloid Precursor Protein Secretases (NLM Chemicals)
KW  - Amyloid beta-Protein Precursor (NLM Chemicals)
KW  - Amyloid beta-Peptides (NLM Chemicals)
KW  - Peptide Fragments (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:41418776
DO  - DOI:10.1016/j.str.2025.11.010
UR  - https://pub.dzne.de/record/285051
ER  -