Recognition of the amyloid precursor protein by human {gamma}-secretase

Cleavage of amyloid precursor protein (APP) by the intramembrane protease -secretase is linked to Alzheimer's disease (AD). We report an atomic structure of human -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 -secretase). A hybrid β sheet, which is formed by a β strand from APP and two β strands from PS1, guides -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 -secretase bound to Notch, reveal contrasting features of substrate binding, which may be applied toward the design of substrate-specific inhibitors.

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