Molecular mechanism of substrate recognition and cleavage by human γ-secretase

• 成果类型: Article
• 署名作者: Guo, Xuefei; Li, Haotian; Yan, Chuangye; Lei, Jianlin; Zhou, Rui; Shi, Yigong
• 署名单位: Tsinghua University; Westlake Laboratory; Westlake University; Westlake University; Westlake University
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-12223
• DOI: 10.1126/science.adn5820
• 发表日期: 2024-06-07
• 页码: 1091-1095
• 关键词: regulated intramembrane proteolysis; amyloid precursor protein; a-beta; alzheimers-disease; intracellular domain; transmembrane domain; presenilin; distinct; mutagenesis; modulation

摘要

Successive cleavages of amyloid precursor protein C-terminal fragment with 99 residues (APP-C99) by gamma-secretase result in amyloid-beta (A beta) peptides of varying lengths. Most cleavages have a step size of three residues. To elucidate the underlying mechanism, we determined the atomic structures of human gamma-secretase bound individually to APP-C99, A beta 49, A beta 46, and A beta 43. In all cases, the substrate displays the same structural features: a transmembrane alpha-helix, a three-residue linker, and a beta-strand that forms a hybrid beta-sheet with presenilin 1 (PS1). Proteolytic cleavage occurs just ahead of the substrate beta-strand. Each cleavage is followed by unwinding and translocation of the substrate alpha-helix by one turn and the formation of a new beta-strand. This mechanism is consistent with existing biochemical data and may explain the cleavages of other substrates by gamma-secretase.