Article | Published:

An atomic structure of human γ-secretase

Nature volume 525, pages 212217 (10 September 2015) | Download Citation

Abstract

Dysfunction of the intramembrane protease γ-secretase is thought to cause Alzheimer’s disease, with most mutations derived from Alzheimer’s disease mapping to the catalytic subunit presenilin 1 (PS1). Here we report an atomic structure of human γ-secretase at 3.4 Å resolution, determined by single-particle cryo-electron microscopy. Mutations derived from Alzheimer’s disease affect residues at two hotspots in PS1, each located at the centre of a distinct four transmembrane segment (TM) bundle. TM2 and, to a lesser extent, TM6 exhibit considerable flexibility, yielding a plastic active site and adaptable surrounding elements. The active site of PS1 is accessible from the convex side of the TM horseshoe, suggesting considerable conformational changes in nicastrin extracellular domain after substrate recruitment. Component protein APH-1 serves as a scaffold, anchoring the lone transmembrane helix from nicastrin and supporting the flexible conformation of PS1. Ordered phospholipids stabilize the complex inside the membrane. Our structure serves as a molecular basis for mechanistic understanding of γ-secretase function.

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Accessions

Primary accessions

Electron Microscopy Data Bank

Protein Data Bank

Data deposits

The atomic coordinates have been deposited in the Protein Data Bank under accession number 5A63, and the EM maps have been deposited in the Electron Microscopy Data Bank under accession code EMD-3061.

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Acknowledgements

We thank S. Chen and C. Savva for support with electron microscopy, and J. Grimmett and T. Darling for support with high-performance computing. This work was supported by funds from the Ministry of Science and Technology (2014ZX09507003006 to Y.S.), the National Natural Science Foundation of China (31130002 and 31321062 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.).

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Author notes

    • Xiao-chen Bai
    • , Chuangye Yan
    •  & Guanghui Yang

    These authors contributed equally to this work.

Affiliations

  1. MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK

    • Xiao-chen Bai
    •  & Sjors H. W. Scheres
  2. Ministry of Education Key Laboratory of Protein Science, Tsinghua-Peking Joint Center for Life Sciences, Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China

    • Chuangye Yan
    • , Guanghui Yang
    • , Peilong Lu
    • , Dan Ma
    • , Linfeng Sun
    • , Rui Zhou
    •  & Yigong Shi

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Contributions

Y.S. initiated and supervised the project. G.Y., P.L., D.M., L.S., and R.Z. prepared the sample and pre-screened samples in various detergents on F20. X.B. prepared grids and collected cryo-EM data. X.B. and S.S. calculated the cryo-EM map. C.Y. built and refined the atomic model. X.B. independently built and refined the atomic model. Y.S., L.S., G.Y., and R.Z. designed and analysed the mutational and biochemical characterizations. L.S., G.Y., and R.Z. performed the biochemical assays. All authors contributed to analysis of the structure. X.B, C.Y., S.S. and Y.S. contributed to manuscript preparation.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Xiao-chen Bai or Sjors H. W. Scheres or Yigong Shi.

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https://doi.org/10.1038/nature14892

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