The complexity of biological membranes and the chemical processes occurring in their context are fascinating and essential for life. Most of the essential functions of biological membranes are performed or catalysed by proteins integrated in or associated with membranes. In fact, a whole 25 to 30% of all protein coding genes in a genome encode transmembrane proteins. The intramembrane proteases are recently discovered and evolutionarily extremely wide-spread alpha-helical transmembrane proteins with the unusual ability to recognise and cleave the transmembrane domains of other membrane proteins within the hydrophobic, lipid environment. How this biochemically unexpected feat is achieved is structurally still poorly understood.

Regulated proteolysis of many integral membrane proteins has major biological consequences. Intramembrane proteases typically activate dormant membrane-bound signaling factors or other membrane proteins and thereby regulate a growing list of biological processes as diverse as developmental and stress signaling, membrane homeostasis, or pathogenicity of microbes. Intramembrane proteases have been implicated in human diseases, including Alzheimer’s, Parkinson’s, immune disorders, cancer and some infectious diseases. Understanding the mechanisms, structures, and regulation of these enzymes can thus open new ways to fight multiple pathological conditions.

We are currently focusing on the nearly ubiquitous intramembrane proteases of the rhomboid family. Rhomboid proteases are known to regulate growth factor signaling in flies, mitochondrial dynamics in yeast or pathogenicity of the malaria parasite, and their proteolytically inactive cousins, rhomboid-like proteins, have been implicated in membrane protein trafficking and quality control. However, the biological functions of most rhomboid-family proteins and their molecular details remain poorly understood or unexplored. In our integrative approach we combine membrane biochemistry, enzymology and structural biology to understand how rhomboid proteases recognise and select substrates, and employ methods of quantitative proteomics, cell biology and genetics to uncover rhomboid functions in selected organisms. We are particularly interested in the basic biological aspects of intramembrane proteolysis relevant for biological signaling, membrane protein biogenesis and homeostasis, but we also exploit the acquired mechanistic insight in the development of rhomboid inhibitors.