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
  • 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.