The γ-secretase complex, comprising presenilin 1 (PS1), PEN-2, APH-1 and nicastrin, is amembrane-embedded protease that controls a number of important cellular functions through substrate cleavage. Aberrant cleavage of the amyloid precursor protein (APP) results in aggregation of amyloid-β, which accumulates in the brain and consequently causes Alzheimer's disease. Here we report the three-dimensional structure of an intact human γ-secretase complex at 4.5A° resolution, determinedbycryo-electron-microscopysingle- particleanalysis.Thec-secretase complexcomprises a horseshoeshaped transmembrane domain, which contains 19 transmembrane segments (TMs), and a large extracellular domain (ECD) fromnicastrin, which sitsimmediately above the hollow space formedby theTMhorseshoe. Intriguingly, nicastrin ECD is structurally similar to a large family of peptidases exemplified by the glutamate carboxypeptidase PSMA. This structure serves as an important basis for understanding the functional mechanisms of the γ-secretase complex.
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