Structural investigation of the active center of gamma-secretase and its interactions with selected substrates

Research project objectives/Hypothesis

The main objective of the project is to reveal a structure of the active center of γ‑secretase membrane-embedded complex and the changes induced by binding selected substrates, including amyloid precursor protein (APP). The project is subdivided into three main stages with the following objectives: (a) modeling of presenilin 1 (PS-1, catalytic subunit of γ‑secretase) active center, (b) investigation of structural changes resulting from selected set of mutations and (c) determination of the influence of those mutations on substrate cleavage, including Aβ42/Aβ40 ratio in case of APP.

Research methodology

The main method used during execution of the project will be molecular dynamics. Data from experimental research on γ-secretase structure will be taken into consideration during planning and execution of the simulations.. The calculation protocol employed will consist of multiple stages in order to obtain active center models of the best possible quality. Since it is possible that new structural data will appear, new unplanned paths may open, including homology modeling procedure based on a better template than those available at the stage of writing this proposal. A presenilin model derived from homology modeling along with refined experimental CTF structure are currently planned to be used in this project.

Research project impact

The knowledge of the active site of γ‑secretase complex may allow for a more detailed elucidation of protein cleavage within membrane boundaries and result in a better design of modulators that will be able to selectively influence APP processing without disrupting the cleavage pathways of other substrates which in turn will finally result in the suppression of further development of AD.