Chemistry

Alpha secretase

Alzheimer's disease

Biochemistry

Protein subunit

Receptor

Cleavage (geology)

Enzyme

Amyloid precursor protein

Amyloid precursor protein secretase

Disease

Membrane

Biology

Scissile bond

Gene

Protease

Cell biology

Transmembrane domain

Transmembrane protein

Pathology

Presenilin

Fracture (geology)

Paleontology

Medicine

Science

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.

Recognition of the amyloid precursor protein by human γ-secretase