Structural basis of Notch recognition by human γ-secretase

@article{Yang2018StructuralBO,
  title={Structural basis of Notch recognition by human $\gamma$-secretase},
  author={Guanghui Yang and Rui Zhou and Qiang Zhou and Xuefei Guo and Chuangye Yan and Meng Ke and Jianlin Lei and Yigong Shi},
  journal={Nature},
  year={2018},
  volume={565},
  pages={192-197}
}
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… 
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An all-atom model of mature wild-type γ-secretase bound to Notch in a complete membrane-water system equilibrated by 3 × 500 nanoseconds of molecular dynamics strongly complements the electron microscopy data and identifies three conformation states that rationalize how Notch cleavage can be imprecise and yield multiple products.
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Substrate recognition and processing by γ-secretase.
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  • 2019
TLDR
Recent findings addressing substrate recognition and processing will be discussed, including the role of protease subunit nicastrin as a gatekeeper, the effects of Alzheimer-causing mutations in presenilin on processive proteolysis of APP, and evidence that three pockets in the active site determine carboxypeptidase cleavage of substrate in intervals of three residues.
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The dynamics of γ-secretase and its substrates.
TLDR
Structural and dynamical features of γ-secretase and its substrates are reviewed including flexibility descriptions from simulations and experiments and further investigations are suggested in order to advance the understanding on howγ- secretase selects and processes substrates.
Modulating Hinge Flexibility in the APP Transmembrane Domain Alters γ-Secretase Cleavage.
TLDR
The data suggest that both enhancing and reducing local helix flexibility of the di-glycine hinge may decrease the occurrence of enzyme-substrate complex conformations required for normal catalysis and that hinge mobility can thus be conducive for productive substrate-enzyme interactions.
Unraveling the complexity of γ-secretase.
  • M. Wolfe
  • Medicine, Biology
    Seminars in cell & developmental biology
  • 2020
TLDR
Substantial progress has been made toward elucidating how γ-secretase carries out complex processing of transmembrane domains, how it goes awry in familial Alzheimer's disease, the scope of its substrates, and the atomic details of its structure.
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