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Three-dimensional structure of human ?-secretase.

ABSTRACT: The ?-secretase complex, comprising presenilin 1 (PS1), PEN-2, APH-1 and nicastrin, is a membrane-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-?, which accumulates in the brain and consequently causes Alzheimer's disease. Here we report the three-dimensional structure of an intact human ?-secretase complex at 4.5 Å resolution, determined by cryo-electron-microscopy single-particle analysis. The ?-secretase complex comprises a horseshoe-shaped transmembrane domain, which contains 19 transmembrane segments (TMs), and a large extracellular domain (ECD) from nicastrin, which sits immediately above the hollow space formed by the TM horseshoe. 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 ?-secretase complex.

SUBMITTER: Lu P

PROVIDER: S-EPMC4134323 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Three-dimensional structure of human γ-secretase.

Lu Peilong P Bai Xiao-Chen XC Ma Dan D Xie Tian T Yan Chuangye C Sun Linfeng L Yang Guanghui G Zhao Yanyu Y Zhou Rui R Scheres Sjors H W SHW Shi Yigong Y

Nature 20140629 7513

The γ-secretase complex, comprising presenilin 1 (PS1), PEN-2, APH-1 and nicastrin, is a membrane-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 4.5 Å resolution, determined by cryo-elect ...[more]

PMID: 25043039

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Three-dimensional structure of human ?-secretase.

Publications

Three-dimensional structure of human γ-secretase.

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