γ-Secretase exosites as targets for substrate-selective lowering of Aβ generation
Year: 2025
Type: article
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.
Source: Structure
Authors: Riki Maruyama, Akio Fukumori, Satoru Funamoto, Ken Okada, Shoshin Akamine, Kanta Yanagida, Mitsuru Shinohara, Naoyuki Sato, Masayasu Okochi, Takashi Kudo, Harald Steiner
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $9,350
Funders: Takeda Science Foundation, Japan Agency for Medical Research and Development, Aichi Health Promotion Foundation, Deutsche Forschungsgemeinschaft, Ichiro Kanehara Foundation for the Promotion of Medical Sciences and Medical Care, SENSHIN Medical Research Foundation, Terumo Foundation for Life Sciences and Arts, Japan Health Foundation, Japan Society for the Promotion of Science, Japan Science and Technology Agency
Awards: ゼロカーボンバイオ産業創出による資源循環共創拠点, G1732028665, G1971558845, 基質結合部位を標的とする副作用を抑えたアルツハイマー病の治療薬開発, Elucidation of the mechanism of exosite and its application to the treatment of Alzheimer's disease, Understanding of A potential defense mechanism against amyloid deposition in cerebellum, FOR 2290: Intramembrane Proteolyse Verstehen, G7249496584
OpenAlex ID: W4417535369