Intramembrane proteases cleave their substrates within the plane of the membrane. Thereby, these unusual proteases affect a wide range of important biological functions and are implicated in several severe diseases including Alzheimer´s disease (AD), the most common neurodegenerative disease. Despite significant progress within the last years, we do not understand the molecular properties that qualify a substrate as such. It is thus unclear what distinguishes substrates from non-substrates in structural terms. On the one hand, the known substrates exhibit a tremendous diversity of primary structures. On the other hand, only a fraction of single-span proteins is known as substrates and point mutations within them can strongly interfere with their proteolysis. This puzzling discrepancy between seemingly promiscuous and clearly sequence-specific proteolysis of substrates indicates that the latter share structural features that allow for specific recognition and cleavage by a given protease. An intramembrane protease apparently achieves substrate/non-substrate discrimination at several levels. Determining the role of soluble and transmembrane domains at these different levels is the mission of this proposal.
The FOR2290 assembled in this renewal proposal is uniquely qualified to solve the open question of how specificity of intramembrane proteolysis is achieved.