The γ-secretase intramembrane protease complex plays a critical role in multiple cellular processes including Notch signaling and secretion of amyloid β peptides, the accumulation of which causes Alzheimer’s disease (AD). The enzymatic activity of γ-secretase is, therefore, a prime target for intervention in AD and is of major interest. Yet, despite the detailed knowledge of γ-secretase's function in various cellular processes and disease, structural information regarding the complex is extremely limited and its mechanism of action at the molecular level remains poorly understood. We propose to address this challenge by structurally analyzing γ-secretase and its unique mechanism using single particle cryo-electron microscopy (cryo-EM) as a primary tool. While structural approaches, such as X-ray crystallography, struggle in the study of membrane-embedded complexes in general and in the study of γ-secretase in particular, an initial structure has already been produced using single particle cryo-EM, demonstrating the feasibility of the procedure and its great potential.
The host laboratory of Prof. Bart De Strooper is well established in the γ-secretase field, while the applicant, Dr. Nadav Elad, is highly experienced in single particle cryo-EM. Combining our expertise, research will aim at achieving a high-resolution structure in close-to-native conditions, determining subunit arrangement and characterizing functional states of γ-secretase. The proposed project both addresses fundamental biological questions regarding intramembrane proteolysis and has immediate therapeutic implications for AD. Additionally, the project will serve as a platform for future studies of γ-secretase, since numerous unanswered questions regarding its variable composition, interactions with multiple substrates and modulators, and its functional mutations, require structural-functional analysis.
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