Allosteric regulation of γ-secretase activity by a phenylimidazole-type γ-secretase modulator

@article{Takeo2014AllostericRO,
  title={Allosteric regulation of $\gamma$-secretase activity by a phenylimidazole-type $\gamma$-secretase modulator},
  author={Koji Takeo and S. Tanimura and Takehiro Shinoda and Satoko Osawa and Ivan Krasmirov Zahariev and Naoki Takegami and Yoshiko Ishizuka-Katsura and Naoko Shinya and Shizuka Takagi-Niidome and Aya Tominaga and Noboru Ohsawa and Tomomi Kimura-Someya and Mikako Shirouzu and Satoshi Yokoshima and Shigeyuki Yokoyama and Tohru Fukuyama and Taisuke Tomita and Takeshi Iwatsubo},
  journal={Proceedings of the National Academy of Sciences},
  year={2014},
  volume={111},
  pages={10544 - 10549}
}
Significance For mechanism-based development of treatment for Alzheimer’s disease (AD), the precise molecular mechanism of γ-secretase modulators (GSMs), which have been extensively developed as possible therapeutic reagents, is required. Here, we analyzed the mode of actions of phenylimidazole-type GSMs using a chemical biology approach and systematic mutagenesis. We provide the first structural model, to our knowledge, that binding of the phenylimidazole-type GSMs at the luminal loop of… Expand
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TLDR
This work proposes a model for the molecular mechanism of phenylimidazole-type GSMs, in which the trimming activity of γ-secretase is modulated by the position of the TMD1 of PS1 in the lipid bilayer, and highlights the importance of the structural dynamics of presenilin 1 in the complexed process of the intramembrane cleavage. Expand
Computational prediction and molecular mechanism of γ-secretase modulators.
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  • Chemistry, Medicine
  • European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences
  • 2020
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The results are consistent with the FIST model of γ-secretase action and suggest that GSMs work in two ways: the binding affinity itself contributes stability to the ternary enzyme-modulator-substrate complex (tight grabbing), thus preventing early release of the substrate and increasing trimming to shorter, innocent Aβ peptides. Expand
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Methods to investigate how GSMs affect the activity of the enzyme as well as how their molecular targets are identified are described. Expand
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Allosteric Modulation of Intact γ-Secretase Structural Dynamics.
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Several factors that can allosterically influence conformational status of the enzyme, and hence the production of Aβ peptides are reviewed, including genetic variations in PS1, APP and other γ-secretase components, environmental stressors implicated in AD pathogenesis and pharmacological agents. Expand
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γ-secretase is a membrane protease complex that catalyzes the cleavage of the amyloid precursor protein to produce the infamous Aβ peptides involved in Alzheimer’s disease (AD). Major efforts aim toExpand
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References

SHOWING 1-10 OF 51 REFERENCES
Phenylpiperidine‐type γ‐secretase modulators target the transmembrane domain 1 of presenilin 1
TLDR
It is shown that a phenylpiperidine‐type compound GSM‐1 directly targets the transmembrane domain (TMD) 1 of presenilin 1 (PS1) by photoaffinity labelling experiments combined with limited digestion, indicating an allosteric action of G SM‐1 by directly binding to the TMD1 of PS1, pinpointing the target structure of the phenylmethine‐type GSMs. Expand
Novel γ-Secretase Enzyme Modulators Directly Target Presenilin Protein*
TLDR
It is demonstrated by using a biotinylated photocross-linkable derivative of highly potent novel second generation GSMs that γ-secretase is a direct target of GSMs, and allosteric modulation of enzyme activity as a mechanism of GSM action is established. Expand
Substrate docking to γ-secretase allows access of γ-secretase modulators to an allosteric site
TLDR
A fluorescence resonance energy transfer-based assay is used to examine whether γ-secretase modulators alter Presenilin-1/γ- secretase conformation in intact cells in the absence of its natural substrates such as amyloid precursor protein and Notch. Expand
Piperidine acetic acid based γ-secretase modulators directly bind to Presenilin-1.
TLDR
Clickable photoaffinity probes based on piperidine acetic acid GSM-1 are developed and identified PS1 as the target within the γ-secretase complex and there is evidence that allosteric interaction of GSMs with PS1 results in a conformational change in the active site of theγ- secretase complex leading to the observed modulation of γ -secretase activity. Expand
γ-Secretase Modulator (GSM) Photoaffinity Probes Reveal Distinct Allosteric Binding Sites on Presenilin*
TLDR
The photoaffinity probe E2012-BPyne specifically labels the N-terminal fragment of presenilin-1 (PS1-NTF) in cell membranes as well as in live cells and primary neuronal cultures providing evidence for multiple binding sites within γ-secretase that confer specific modulatory effects. Expand
Signature Amyloid β Profiles Are Produced by Different γ-Secretase Complexes*
TLDR
It is found that the nature of the catalytic subunit in the complex affects both activities, and each γ-secretase complex produces a characteristic Aβ signature, which could be used to advance drug development in AD and other disorders. Expand
Sulindac Sulfide Is a Noncompetitive γ-Secretase Inhibitor That Preferentially Reduces Aβ42 Generation*
Nonsteroidal anti-inflammatory drugs (NSAIDs) have been known to reduce risk for Alzheimer's disease. In addition to the anti-inflammatory effects of NSAIDs to block cylooxygenase, it has been shownExpand
Activation and intrinsic γ-secretase activity of presenilin 1
TLDR
It is conclusively established that activated PS is catalytically competent and the bimolecular interaction of PS1 and PEN2 can convert the PS1 zymogen to an active protease, which means that γ-secretase cleavage specificity is an inherent property of the polypeptide. Expand
γ-Secretase Heterogeneity in the Aph1 Subunit: Relevance for Alzheimer’s Disease
TLDR
Specific inactivation of the Aph1B γ-secretase in a mouse Alzheimer's disease model led to improvements of Alzheimer’s disease–relevant phenotypic features without any Notch-related side effects, and thus specific targeting of Aph1 B-containing γ -secretase complexes may help generate less toxic therapies for Alzheimer”s disease. Expand
Binding of longer Aβ to transmembrane domain 1 of presenilin 1 impacts on Aβ42 generation
TLDR
It is found that the transmembrane domain (TMD) 1 of presenilin (PS1) 1, a catalytic subunit for the γ-secretase, as a key modulatory domain for Aβ42 production, and that the helical surface of TMD1 is involved in the binding of Aβ45/48 and the binding was altered by GSMs as well as T MD1 mutation. Expand
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