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Structural basis of Notch recognition by human γ-secretase

Author

Listed:
  • Guanghui Yang

    (Tsinghua University)

  • Rui Zhou

    (Tsinghua University)

  • Qiang Zhou

    (Tsinghua University
    Westlake Institute for Advanced Study)

  • Xuefei Guo

    (Tsinghua University)

  • Chuangye Yan

    (Tsinghua University)

  • Meng Ke

    (Tsinghua University)

  • Jianlin Lei

    (Tsinghua University
    Tsinghua University)

  • Yigong Shi

    (Tsinghua University
    Westlake Institute for Advanced Study)

Abstract

Aberrant cleavage of Notch by γ-secretase leads to several types of cancer, but how γ-secretase recognizes its substrate remains unknown. Here we report the cryo-electron microscopy structure of human γ-secretase in complex with a Notch fragment at a resolution of 2.7 Å. The transmembrane helix of Notch is surrounded by three transmembrane domains of PS1, and the carboxyl-terminal β-strand of the Notch fragment forms a β-sheet with two substrate-induced β-strands of PS1 on the intracellular side. Formation of the hybrid β-sheet is essential for substrate cleavage, which occurs at the carboxyl-terminal end of the Notch transmembrane helix. PS1 undergoes pronounced conformational rearrangement upon substrate binding. These features reveal the structural basis of Notch recognition and have implications for the recruitment of the amyloid precursor protein by γ-secretase.

Suggested Citation

  • Guanghui Yang & Rui Zhou & Qiang Zhou & Xuefei Guo & Chuangye Yan & Meng Ke & Jianlin Lei & Yigong Shi, 2019. "Structural basis of Notch recognition by human γ-secretase," Nature, Nature, vol. 565(7738), pages 192-197, January.
    • Handle: RePEc:nat:nature:v:565:y:2019:i:7738:d:10.1038_s41586-018-0813-8
    DOI: 10.1038/s41586-018-0813-8
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    Cited by:

    1. Ivica Odorčić & Mohamed Belal Hamed & Sam Lismont & Lucía Chávez-Gutiérrez & Rouslan G. Efremov, 2024. "Apo and Aβ46-bound γ-secretase structures provide insights into amyloid-β processing by the APH-1B isoform," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    2. Xia Wang & Jiayu Wang & Yashuang Chen & Xiaojing Qian & Shiqi Luo & Xue Wang & Chao Ma & Wei Ge, 2024. "The aldehyde dehydrogenase 2 rs671 variant enhances amyloid β pathology," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    3. Xuefei Guo & Yumeng Wang & Jiayao Zhou & Chen Jin & Jiaoni Wang & Bojun Jia & Dan Jing & Chuangye Yan & Jianlin Lei & Rui Zhou & Yigong Shi, 2022. "Molecular basis for isoform-selective inhibition of presenilin-1 by MRK-560," Nature Communications, Nature, vol. 13(1), pages 1-7, December.
    4. Melanie A. Orlando & Hunter J. T. Pouillon & Saikat Mandal & Lee Kroos & Benjamin J. Orlando, 2024. "Substrate engagement by the intramembrane metalloprotease SpoIVFB," Nature Communications, Nature, vol. 15(1), pages 1-13, December.

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