Structural basis of Notch recognition by human γ-secretase

Nature. 2019 Jan;565(7738):192-197. doi: 10.1038/s41586-018-0813-8.

Guanghui Yang ^# ¹, Rui Zhou ^# ¹, Qiang Zhou ¹ ², Xuefei Guo ¹, Chuangye Yan ¹, Meng Ke ¹, Jianlin Lei ¹ ³, Yigong Shi ⁴ ⁵

Affiliations

1 Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China.
2 Institute of Biology, Westlake Institute for Advanced Study, Hangzhou, China.
3 Technology Center for Protein Sciences, Ministry of Education Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, Beijing, China.
4 Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China. shi-lab@tsinghua.edu.cn.
5 Institute of Biology, Westlake Institute for Advanced Study, Hangzhou, China. shi-lab@tsinghua.edu.cn.
# Contributed equally.

PMID: 30598546 DOI: 10.1038/s41586-018-0813-8

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.

Name
Email *

	Sorry, but the email address you supplied was invalid.