Research Article

Recognition of the amyloid precursor protein by human γ-secretase

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Science  10 Jan 2019:
eaaw0930
DOI: 10.1126/science.aaw0930

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Abstract

Cleavage of amyloid precursor protein (APP) by the intramembrane protease γ-secretase is linked to Alzheimer’s disease. We report an atomic structure of human γ-secretase in complex with a transmembrane APP fragment at 2.6-Å resolution. The transmembrane helix (TM) 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 exploited toward design of substrate-specific inhibitors.

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