Three-dimensional structure of human γ-secretase

Peilong Lu, Xiao-chen Bai, Dan Ma, Tian Xie, Chuangye Yan, Linfeng Sun, Guanghui Yang, Yanyu Zhao, Rui Zhou, Sjors H. W. Scheres () and Yigong Shi ()
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Peilong Lu: Ministry of Education Key Laboratory of Protein Science, Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University
Xiao-chen Bai: MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK
Dan Ma: Ministry of Education Key Laboratory of Protein Science, Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University
Tian Xie: Ministry of Education Key Laboratory of Protein Science, Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University
Chuangye Yan: Tsinghua-Peking Joint Center for Life Sciences, Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University
Linfeng Sun: Ministry of Education Key Laboratory of Protein Science, Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University
Guanghui Yang: Tsinghua-Peking Joint Center for Life Sciences, Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University
Yanyu Zhao: Ministry of Education Key Laboratory of Protein Science, Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University
Rui Zhou: Ministry of Education Key Laboratory of Protein Science, Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University
Sjors H. W. Scheres: MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK
Yigong Shi: Ministry of Education Key Laboratory of Protein Science, Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University

Nature, 2014, vol. 512, issue 7513, 166-170

Abstract: Abstract 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-electron-microscopy single-particle analysis. The γ-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 γ-secretase complex.

Date: 2014
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DOI: 10.1038/nature13567

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