SUMMARY
γ-Secretase is composed of four proteins that are obligatory for protease activity: Presenilin, Nicastrin, Aph1 and Pen-2. Despite the progress towards understanding the function of these individual subunits, there is no information available pertaining to the modulation of γ-secretase in response to environmental changes in cells. Here we show that hypoxia upregulates γ-secretase activity through a direct interaction with Hif-1α, revealing an unconventional function for Hif-1α as an enzyme subunit, which is distinct from its canonical role as a transcription factor. Moreover, hypoxia-induced cell invasion and metastasis are alleviated by either γ-secretase inhibitors or a dominant negative Notch coactivator, indicating that γ-secretase/Notch signaling plays an essential role in controlling these cellular processes. The present study reveals an unprecedented mechanism in which γ-secretase can achieve temporal control through conditional interactions with regulatory proteins, such as Hif-1α, under select physiological and pathological conditions.
Background:The effect of PS1 mutations on the active site of ␥-secretase is unknown. Results: PS1 mutations reduce photoprobe interaction with the S2 subsite of ␥-secretase and Notch1 cleavage. Conclusion: Certain PS mutations specifically alter the S2 subsite of ␥-secretase active site that leads to changes in APP and Notch1 cleavage. Significance: It provides structural insights into the mechanism of PS1 mutations in regards to ␥-secretase regulation.
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