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Nature. 2014 Aug 14;512(7513):166-170. doi: 10.1038/nature13567. Epub 2014 Jun 29.

Three-dimensional structure of human γ-secretase.

Lu P#1,2, Bai XC#3, Ma D#1,2, Xie T1,2, Yan C4,2, Sun L1,2, Yang G4,2, Zhao Y1,2, Zhou R1,2, Scheres SHW3, Shi Y1,2.

Author information

1
Ministry of Education Key Laboratory of Protein Science, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.
2
Tsinghua-Peking Joint Center for Life Sciences, Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.
3
MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK.
4
State Key Laboratory of Bio-membrane and Membrane Biotechnology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.
#
Contributed equally

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.

PMID:
25043039
PMCID:
PMC4134323
DOI:
10.1038/nature13567
[Indexed for MEDLINE]
Free PMC Article

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