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Proposing Institution

Biopolymer Chemistry,TU München
Project Manager

Dr. Christina Scharnagl
Maximus-von-Imhof-Forum 4
85354 Freising
Intramembrane proteases affect a wide range of important biologicalfunctions and are implicated in several diseases includingAlzheimer's disease. More than a decade of research revealed apuzzling discrepancy between seemingly promiscuous and clearlysite-specific processing of their substrates, which indicates thatsubstrates of transmembrane domains share structural or dynamicalfeatures that allow for specific recognition and cleavage by a givenprotease. To solve the open question of how specificity ofintramembrane proteolysis is achieved, our project will explore howproteolysis is related to the structure and conformationalflexibility of the substrate transmembrane helices using moleculardynamics methods. This entails also investigating the effect ofdisease-associated substrate mutations. Since intramembraneproteases are considered as relevant drug targets a deep knowledgeof their cleavage mechanism is crucial in order to developinhibitors and/or modulators.We will use established multi-copy methods seeded from a largenumber of start structures for an exhaustive sampling of theconformational ensemble of a few experimentally well-characterizedmodel substrates of intramembrane protease. In a second approach, wewill focus on large-scale collective motion, which inform about thedirections of conformational transitions (dynamic fingerprints). Wewill compare the dynamic fingerprints of 150 intramembrane proteasesubstrates and non-substrates.

Impressum, Conny Wendler