2. Academic Validation
  3. Three-dimensional structure of human γ-secretase

Three-dimensional structure of human γ-secretase

  • Nature. 2014 Aug 14;512(7513):166-170. doi: 10.1038/nature13567.
Peilong Lu # 1 2,  Xiao-Chen Bai # 3,  Dan Ma # 1 2,  Tian Xie 1 2,  Chuangye Yan 4 2,  Linfeng Sun 1 2,  Guanghui Yang 4 2,  Yanyu Zhao 1 2,  Rui Zhou 1 2,  Sjors H W Scheres 3,  Yigong Shi 1 2
Affiliations

Affiliations

  • 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.
PMID: 25043039 DOI: 10.1038/nature13567
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.

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