Recognition of the amyloid precursor protein by human γ-secretase

Science
Rui ZhouYigong Shi

Abstract

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.

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Related Concepts

APP protein, human
Alpha-Helical Conformation, Protein
Beta-Sheet Conformation, Protein
Familial Alzheimer Disease (FAD)
Amyloid beta-Protein Precursor
Catalytic Domain
Cryoelectron Microscopy
Receptors, Notch
Gamma-Secretase
Protein Digestion

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