title: Three-dimensional structure of human γ-secretase.
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.
authors.affiliation: Ministry of Education Key Laboratory of Protein Science, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.|Tsinghua-Peking Joint Center for Life Sciences, Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.
authors.forename: Peilong
authors.initials: P
authors.lastname: Lu
authors.affiliation: MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK.
authors.forename: Xiao-Chen
authors.initials: XC
authors.lastname: Bai
authors.affiliation: Ministry of Education Key Laboratory of Protein Science, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.|Tsinghua-Peking Joint Center for Life Sciences, Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Ma
authors.affiliation: Ministry of Education Key Laboratory of Protein Science, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.|Tsinghua-Peking Joint Center for Life Sciences, Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.
authors.forename: Tian
authors.initials: T
authors.lastname: Xie
authors.affiliation: State Key Laboratory of Bio-membrane and Membrane Biotechnology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.|Tsinghua-Peking Joint Center for Life Sciences, Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.
authors.forename: Chuangye
authors.initials: C
authors.lastname: Yan
authors.affiliation: Ministry of Education Key Laboratory of Protein Science, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.|Tsinghua-Peking Joint Center for Life Sciences, Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.
authors.forename: Linfeng
authors.initials: L
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Bio-membrane and Membrane Biotechnology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.|Tsinghua-Peking Joint Center for Life Sciences, Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.
authors.forename: Guanghui
authors.initials: G
authors.lastname: Yang
authors.affiliation: Ministry of Education Key Laboratory of Protein Science, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.|Tsinghua-Peking Joint Center for Life Sciences, Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.
authors.forename: Yanyu
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Ministry of Education Key Laboratory of Protein Science, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.|Tsinghua-Peking Joint Center for Life Sciences, Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhou
authors.affiliation: MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK.
authors.forename: Sjors H W
authors.initials: SHW
authors.lastname: Scheres
authors.affiliation: Ministry of Education Key Laboratory of Protein Science, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.|Tsinghua-Peking Joint Center for Life Sciences, Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.
authors.forename: Yigong
authors.initials: Y
authors.lastname: Shi
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000737:chemistry*; D020285:Cryoelectron Microscopy; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D017434:Protein Structure, Tertiary
chemical_list: D053829:Amyloid Precursor Protein Secretases