资源环境科技发展态势分析平台

Cleavage of amyloid precursor protein (APP) by the intramembrane protease gamma-secretase is linked to Alzheimer's disease (AD). We report an atomic structure of human gamma-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 gamma-secretase). A hybrid beta sheet, which is formed by a beta strand from APP and two beta strands from PS1, guides gamma-secretase to the scissile peptide bond of APP between its TM and b strand. Residues at the interface between PS1 and APP are heavily targeted by recurring mutations from AD patients. This structure, together with that of gamma-secretase bound to Notch, reveal contrasting features of substrate binding, which may be applied toward the design of substrate-specific inhibitors.