Intramembrane proteolysis by γ-secretase


The etiology of Alzheimer’s disease depends on cleavage of the amyloid precursor protein TMD by γ-secretase where the toxic Aβ peptides are generated. It is currently unclear how γ-secretase recognizes and cleaves the Alzheimer protein TMD and certain other substrates. However, it is likely that the substrate TMD is cleaved as a homodimer and that it has to unfold locally to provide access to catalytic residues and water.

The concept:

We compare different substrate and non-substrate TMDs in terms of self-interaction and backbone dynamics to delineate the critical structureal features of intramembrane protease substrates. To this end, a FRET-based interaction assay is developed. To map TMD backbone dynamics, hydrogen/deuterium exchange kinetics of synthetic TMDs are performed and complemented by Molecular dynamics simulations that provide a detailed picture of local dynamics.

Future work may include investigating the lipid dependence of TMD-TMD interaction, the impact of dimerization on helix dynamics, the effect of naturally occuring point mutations and the influence of g-secretase on the structural features of the substrate TMD.