Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
Institute of Biology, Westlake Institute for Advanced Study, Westlake University, 18 Shilongshan Road, Xihu District, Hangzhou 310024, Zhejiang Province, China.
Science. 2019 Feb 15;363(6428). doi: 10.1126/science.aaw0930. Epub 2019 Jan 10.
Cleavage of amyloid precursor protein (APP) by the intramembrane protease γ-secretase is linked to Alzheimer's disease (AD). We report an atomic structure of human γ-secretase in complex with a transmembrane (TM) APP fragment at 2.6-angstrom resolution. The TM helix of APP closely interacts with five surrounding TMs of PS1 (the catalytic subunit of γ-secretase). A hybrid β sheet, which is formed by a β strand from APP and two β strands from PS1, guides γ-secretase to the scissile peptide bond of APP between its TM and β strand. Residues at the interface between PS1 and APP are heavily targeted by recurring mutations from AD patients. This structure, together with that of γ-secretase bound to Notch, reveal contrasting features of substrate binding, which may be applied toward the design of substrate-specific inhibitors.
淀粉样前体蛋白（APP）通过跨膜蛋白酶 γ-分泌酶的裂解与阿尔茨海默病（AD）有关。我们报道了人γ-分泌酶与跨膜 APP 片段在 2.6-埃分辨率下的复合物的原子结构。APP 的跨膜螺旋与 PS1（γ-分泌酶的催化亚基）的五个相邻 TM 紧密相互作用。由 APP 的β 链和 PS1 的两个β 链形成的杂合β 片层，引导 γ-分泌酶到达 APP 的 TM 和 β 链之间的裂解肽键。来自 AD 患者的反复突变严重靶向 PS1 和 APP 之间界面上的残基。该结构与与 Notch 结合的 γ-分泌酶的结构一起，揭示了底物结合的对比特征，这可能应用于设计底物特异性抑制剂。
