Structural basis of Notch recognition by human γ-secretase

Guanghui Yang, Rui Zhou, Qiang Zhou, Xuefei Guo, Chuangye Yan, Meng Ke, Jianlin Lei and Yigong Shi ()
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Guanghui Yang: Tsinghua University
Rui Zhou: Tsinghua University
Qiang Zhou: Tsinghua University
Xuefei Guo: Tsinghua University
Chuangye Yan: Tsinghua University
Meng Ke: Tsinghua University
Jianlin Lei: Tsinghua University
Yigong Shi: Tsinghua University

Nature, 2019, vol. 565, issue 7738, 192-197

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41586-018-0813-8

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