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- W3025573205 abstract "γ-Secretase is an intramembrane aspartyl-protease catalyzing the final step in the regulated intramembrane proteolysis of a large number of single-span type-1 transmembrane proteins. The most extensively studied substrates are the amyloid-β precursor protein (APP) and the NOTCH receptors. An important technique for the characterization of interactions and conformational changes enabling γ-secretase to perform hydrolysis within the confines of the membrane are molecular dynamics simulations on different time and length scales. Here, we review structural and dynamical features of γ−secretase and its substrates including flexibility descriptions from simulations and experiments. We address (1) conformational sampling of apo-enzyme and unbound substrates (exemplified for APP, NOTCH1 and the apparent non-substrate integrin β1), (2) substrate recruitment pathways, (3) conformational changes associated with the formation of the recognition complex, (4) cleavage-site unfolding upon interaction with the enzyme’s active site, (5) substrate processing after endoproteolysis, and (6) inhibition and modulation of γ-secretase. We conclude with still open questions and suggest further investigations in order to advance our understanding on how γ-secretase selects and processes substrates. This knowledge will improve the ability to better target substrates selectively for therapeutic applications." @default.
- W3025573205 created "2020-05-21" @default.
- W3025573205 creator A5002196787 @default.
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- W3025573205 creator A5027262483 @default.
- W3025573205 creator A5038552808 @default.
- W3025573205 creator A5090330416 @default.
- W3025573205 date "2020-09-01" @default.
- W3025573205 modified "2023-10-13" @default.
- W3025573205 title "The dynamics of γ-secretase and its substrates" @default.
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