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Proposing Institution

Lehrstuhl für Bioelektronik (E14) ,TUM
Project Manager

Dr. Christina Scharnagl
Masximus-von.Imhof Forum 4
85354 Freising
Regulated intramembrane proteolysis controls the activity of membrane proteins, i.e. signal transduction and control of cell differentiation as well as degradation of faulty proteins. The process appears to be tightly regulated, and deregulation is associated with diseases like Alzheimer's disease. Although the processing of substrates by the intramembrane-cleaving enzyme gamma-secretase has been worked out in great detail, determinants and mechanisms of substrate recognition and cleavage are still unclear. Previous work focussed on the dynamical architecture of the substrate's transmembrane domain carrying the cleavage sites. However, our extensive molecular dynamic simulations revealed diverse dynamical pattern which do not differentiate between substrates and non-substrates. Current experimental evidence points to the vital roles of the membrane environment, of conformational changes within the enzyme and of the extra- and intracellular domains flanking the transmembrane domain. By significantly extending our previous work, we will use molecular dynamics simulations on coarse-grained and all-atom scale of full-length substrates and non-substrates interacting with the enzyme gamma-secretase in model membranes with different compositions. The work is part of a collaborative research project (Forschergruppe FOR2290, funded by DFG, https://www.i-proteolysis.de) and will provide a deeper understanding of determinants and mechanisms for substrate recognition and processing.

Impressum, Conny Wendler