title: Crystal structure of the γ-secretase component nicastrin.
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 nicastrin 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 hydrophobic 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.
authors.affiliation: Ministry of Education Key Laboratory of Protein Science, 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: Tsinghua-Peking Joint Center for Life Sciences, Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China State Key Laboratory of Bio-Membrane and Membrane Biotechnology, and.
authors.forename: Chuangye
authors.initials: C
authors.lastname: Yan
authors.affiliation: Ministry of Education Key Laboratory of Protein Science, 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: Ministry of Education Key Laboratory of Protein Science, 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, 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: Tsinghua-Peking Joint Center for Life Sciences, Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China State Key Laboratory of Bio-Membrane and Membrane Biotechnology, and.
authors.forename: Guanghui
authors.initials: G
authors.lastname: Yang
authors.affiliation: Ministry of Education Key Laboratory of Protein Science, 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: Ministry of Education Key Laboratory of Protein Science, 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, Tsinghua-Peking Joint Center for Life Sciences, Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China shi-lab@tsinghua.edu.cn.
authors.forename: Yigong
authors.initials: Y
authors.lastname: Shi
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000737:chemistry*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004023:Dictyostelium / Q000201:enzymology*; D006801:Humans; D008562:Membrane Glycoproteins / Q000737:chemistry*; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D013379:Substrate Specificity
chemical_list: D008562:Membrane Glycoproteins; C413604:nicastrin protein; D053829:Amyloid Precursor Protein Secretases