Intramembrane proteolytic systems: mechanisms, regulation and biological roles

We are fascinated by the complexity of biological membranes and the chemical processes occurring in their context. In particular, we are interested in intramembrane proteases - enzymes with the unusual ability to recognise and cleave the transmembrane domains of other membrane proteins within the hydrophobic milieu of lipid membranes. This unexpected biochemical reaction typically results in the activation of dormant signaling factors or activation of resident membrane proteins. About 25 to 30% of all proteins encoded in a genome are transmembrane, and controlled proteolysis of many of them has major biological consequences. Intramembrane proteases thus regulate a growing list of biological processes as diverse as developmental and stress signaling, membrane homeostasis, or pathogenicity of microbes. They have been implicated in human diseases including Alzheimer's, Parkinson's and some infectious diseases, which has fuelled the interest in these unusual enzymes.

We are currently focusing on the evolutionarily nearly ubiquitous intramembrane protases of the rhomboid family. Rhomboids are known to regulate growth factor signaling in flies, mitochondrial dynamics in yeast or pathogenicity of the malaria parasite, but their functions in nearly all bacteria or mammals remain unexplored. In our integrative approach we combine membrane biochemistry, enzymology and structural biology to understand how rhomboids recognise and select substrates, and employ methods of quantitative proteomics, cell biology and genetics to define their substrate repertoires, ultimately aiming to uncover their biological functions in selected organisms. We are particularly interested in the basic biological aspects of intramembrane proteolysis by rhomboids relevant for biological signaling, membrane protein biogenesis and homeostasis, but we also aim to exploit the acquired mechanistic insight practically in contributing to the development of specific inhibitors of rhomboids. Please use the links on the left to find out more about us and our research.