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γ-Secretase, called “the proteasome of the membrane,” is a membrane-embedded protease complex that cleaves 150+ peptide substrates with central roles in biology and medicine, including amyloid precursor protein and the Notch family of cell-surface receptors. Mutations in γ-secretase and amyloid precursor protein lead to early-onset familial Alzheimer’s disease. γ-Secretase has thus served as a critical drug target for treating familial Alzheimer’s disease and the more common late-onset Alzheimer’s disease as well. However, critical gaps remain in understanding the mechanisms of processive proteolysis of substrates, the effects of familial Alzheimer’s disease mutations, and allosteric modulation of substrate cleavage by γ-secretase. In this review, we focus on recent studies of structural dynamic mechanisms of γ-secretase. Different mechanisms, including the “Fit-Stay-Trim,” “Sliding-Unwinding,” and “Tilting-Unwinding,” have been proposed for substrate proteolysis of amyloid precursor protein by γ-secretase based on all-atom molecular dynamics simulations. While an incorrect registry of the Notch1 substrate was identified in the cryo-electron microscopy structure of Notch1-bound γ-secretase, molecular dynamics simulations on a resolved model of Notch1-bound γ-secretase that was reconstructed using the amyloid precursor protein-bound γ-secretase as a template successfully captured γ-secretase activation for proper cleavages of both wildtype and mutant Notch, being consistent with biochemical experimental findings. The approach could be potentially applied to decipher the processing mechanisms of various substrates by γ-secretase. In addition, controversy over the effects of familial Alzheimer’s disease mutations, particularly the issue of whether they stabilize or destabilize γ-secretase-substrate complexes, is discussed. Finally, an outlook is provided for future studies of γ-secretase, including pathways of substrate binding and product release, effects of modulators on familial Alzheimer’s disease mutations of the γ-secretase-substrate complexes. Comprehensive understanding of the functional mechanisms of γ-secretase will greatly facilitate the rational design of effective drug molecules for treating familial Alzheimer’s disease and perhaps Alzheimer’s disease in general.
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Computational insights into lipid assisted peptide misfolding and aggregation in neurodegeneration
Peptide misfolding and aberrant assembly in membranous micro-environments have been associated with numerous neurodegenerative diseases. The biomolecular mechanisms and biophysical implications of these amyloid membrane interactions have been under extensive research and can assist in understanding disease pathogenesis and potential development of rational therapeutics. But, the complex nature and diversity of biomolecular interactions, structural transitions, and dependence on local environmental conditions have made accurate microscopic characterization challenging. In this review, using cases of Alzheimer's disease (amyloid-beta peptide), Parkinson's disease (alpha-synuclein peptide) and Huntington's disease (huntingtin protein), we illustrate existing challenges in experimental investigations and summarize recent relevant numerical simulation studies into amyloidogenic peptide–membrane interactions. In addition we project directions for future in silico studies and discuss shortcomings of current computational approaches.
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- PAR ID:
- 10174897
- Date Published:
- Journal Name:
- Physical Chemistry Chemical Physics
- Volume:
- 21
- Issue:
- 41
- ISSN:
- 1463-9076
- Page Range / eLocation ID:
- 22679 to 22694
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1039/C9CP02765C
