Article | Published:

Three-dimensional structure of human γ-secretase

Nature volume 512, pages 166170 (14 August 2014) | Download Citation

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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Accessions

Primary accessions

Electron Microscopy Data Bank

Protein Data Bank

Data deposits

The modelled atomic coordinates of nicastrin has been deposited in the Protein Data Bank with the accession code 4UPC. In addition, the 4.5 Å and 5.4 Å EM maps have been deposited in EMDB with accession codes EMD-2677 and EMD-2678, respectively.

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Acknowledgements

We thank M. Wolfe and D. Selkoe for support and encouragement, and S. Chen, C. Savva, J. Grimmett and T. Darling for technical support. This work was funded by the Ministry of Science and Technology of China (2009CB918801 to Y.S.), National Natural Science Foundation of China (projects 30888001, 31021002 and 31130002 to Y.S.), a European Union Marie Curie Fellowship (to X.C.B.), and the UK Medical Research Council (MC_UP_A025_1013, to S.H.W.S.).

Author information

Author notes

    • Peilong Lu
    • , Xiao-chen Bai
    •  & Dan Ma

    These authors contributed equally to this work.

Affiliations

  1. Ministry of Education Key Laboratory of Protein Science, Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China

    • Peilong Lu
    • , Dan Ma
    • , Tian Xie
    • , Linfeng Sun
    • , Yanyu Zhao
    • , Rui Zhou
    •  & Yigong Shi
  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

    • Peilong Lu
    • , Dan Ma
    • , Tian Xie
    • , Chuangye Yan
    • , Linfeng Sun
    • , Guanghui Yang
    • , Yanyu Zhao
    • , Rui Zhou
    •  & Yigong Shi
  3. MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK

    • Xiao-chen Bai
    •  & Sjors H. W. Scheres
  4. State Key Laboratory of Bio-membrane and Membrane Biotechnology, Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China

    • Chuangye Yan
    •  & Guanghui Yang

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Contributions

P.L., X.B., D.M., S.H.W.S. and Y.S. designed all experiments. P.L., X.B., D.M., T.X., C.Y., L.S., G.Y., Y.Z. and R.Z. performed the experiments. All authors contributed to data analysis. P.L., X.B., D.M., S.H.W.S. and Y.S. contributed to manuscript preparation.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Sjors H. W. Scheres or Yigong Shi.

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https://doi.org/10.1038/nature13567

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