Crystal structure of the γ-secretase component nicastrin

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Abstract

γ-Secretase is an intramembrane protease responsible for the generation of amyloid-β (Aβ) peptides. Aberrant accumulation of Aβ leads to the formation of amyloid plaques in the brain of patients with Alzheimer's disease. Nicastrin is the putative substrate-recruiting component of the γ-secretase complex. No atomic-resolution structure had been identified on γ-secretase or any of its four components, hindering mechanistic understanding of γ-secretase function. Here we report the crystal structure of nicas-trin from Dictyostelium purpureum at 1.95-Å resolution. The extracellular domain of nicastrin contains a large lobe and a small lobe. The large lobe of nicastrin, thought to be responsible for substrate recognition, associates with the small lobe through a hy-drophobic pivot at the center. The putative substrate-binding pocket is shielded from the small lobe by a lid, which blocks substrate entry. These structural features suggest a working model of nicastrin function. Analysis of nicastrin structure provides insights into the assembly and architecture of the γ-secretase complex.

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Xie, T., Yan, C., Zhou, R., Zhao, Y., Sun, L., Yang, G., … Shi, Y. (2014). Crystal structure of the γ-secretase component nicastrin. Proceedings of the National Academy of Sciences of the United States of America, 111(37), 13349–13354. https://doi.org/10.1073/pnas.1414837111

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