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Substrate recruitment by γ-secretase.

Akio Fukumori1, Lukas P Feilen2, Harald Steiner3

  • 1Department of Aging Neurobiology, National Center for Geriatrics and Gerontology, Morioka-cho 7-430, 474-8511, Obu, Japan; Department of Mental Health Promotion, Osaka University Graduate School of Medicine, Machikaneyama-cho 1-17, 560-0043, Toyonaka, Japan.

Seminars in Cell & Developmental Biology
|April 26, 2020
PubMed
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Gamma-secretase, crucial for Alzheimer's disease (AD) and cell differentiation, cleaves amyloid precursor protein (APP) and Notch1. Recent advances in biochemical and structural biology studies are revealing how this enzyme recruits and cleaves its substrates.

Keywords:
Alzheimer’s diseaseAmyloid β-peptideFamilial Alzheimer’s diseaseIntramembrane proteolysisPresenilinγ-Secretase

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Neuroscience

Background:

  • Gamma-secretase is a critical intramembrane protease complex involved in vital physiological processes.
  • Its role in Alzheimer's disease (AD) pathogenesis, particularly familial forms, makes it a significant drug target.
  • Gamma-secretase cleaves amyloid precursor protein (APP) into amyloid-beta peptides (Aβ), including neurotoxic Aβ42, and Notch1, essential for cell differentiation.

Purpose of the Study:

  • To review recent progress in understanding how gamma-secretase recognizes and recruits its substrates.
  • To elucidate the mechanisms of intramembrane proteolytic cleavage by the gamma-secretase complex.
  • To highlight recent insights from biochemical and structural biology studies.

Main Methods:

  • Literature review of biochemical studies.
  • Analysis of structural biology data.
  • Integration of findings on substrate recognition and recruitment.

Main Results:

  • Progress has been made in understanding substrate recruitment and recognition by gamma-secretase.
  • Biochemical and structural studies are beginning to reveal the mechanisms of intramembrane proteolysis.
  • The complex process of substrate interaction with the catalytic subunit, presenilin, is becoming clearer.

Conclusions:

  • Understanding gamma-secretase substrate interaction is advancing rapidly.
  • Recent biochemical and structural insights are key to deciphering this enzyme's function.
  • Further research promises to unlock the secrets of gamma-secretase-mediated cleavage.