劈理(地质)
连接器
化学
跨膜结构域
早老素
淀粉样前体蛋白
生物物理学
跨膜蛋白
立体化学
螺旋(腹足类)
生物化学
生物
膜
生态学
计算机科学
蜗牛
疾病
阿尔茨海默病
受体
古生物学
病理
操作系统
医学
断裂(地质)
作者
Xuefei Guo,H. D. Li,Chuangye Yan,Jianlin Lei,Rui Zhou,Yigong Shi
出处
期刊:Science
[American Association for the Advancement of Science (AAAS)]
日期:2024-06-06
卷期号:384 (6700): 1091-1095
被引量:1
标识
DOI:10.1126/science.adn5820
摘要
Successive cleavages of amyloid precursor protein C-terminal fragment with 99 residues (APP-C99) by γ-secretase result in amyloid-β (Aβ) 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 γ-secretase bound individually to APP-C99, Aβ49, Aβ46, and Aβ43. In all cases, the substrate displays the same structural features: a transmembrane α-helix, a three-residue linker, and a β-strand that forms a hybrid β-sheet with presenilin 1 (PS1). Proteolytic cleavage occurs just ahead of the substrate β-strand. Each cleavage is followed by unwinding and translocation of the substrate α-helix by one turn and the formation of a new β-strand. This mechanism is consistent with existing biochemical data and may explain the cleavages of other substrates by γ-secretase.
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