Structural and mechanistic principles of intramembrane proteolysis – lessons from rhomboids

K. Strisovsky², K. R. Vinothkumar¹, H. Sharpe¹, C. Adrain¹, E. Stevens¹, M. Freeman¹

¹Medical Research Council Laboratory of Molecular Biology, CB2 2QH, Cambridge, United Kingdom

²Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo n. 2, 166 10, Prague, Czech Republic

tel +420-220183468, e-mail kvido.strisovsky@uochb.cas.cz

Intramembrane proteases cleave membrane proteins in their transmembrane domains. This is intriguing, since the hydrophobic interior of lipid membranes excludes water and is thus not an ideal milieu for hydrolytic reactions. But intramembrane proteases are very widespread in evolution and those few that have been studied in detail regulate a variety of prominent biological processes including developmental signalling, stress responses, membrane protein quality control, mitochondrial dynamics and apoptosis. Despite their evolutionary ubiquity and biological significance, our mechanistic and structural understanding of these enzymes is limited. There are three catalytic types of intramembrane proteases, their active sites are buried in the lipid membrane and they are all evolutionarily unrelated to the “classical“, soluble proteases. Significant progress has been made in understanding their function during the past few years, but fundamental structural and mechanistic questions are still open. How do intramembrane proteases recognise their transmembrane substrates and how do they achieve specificity? How does water gain access to the membrane-immersed catalytic site? What is the mechanism of the cleavage reaction? Using rhomboid intramembrane serine proteases as a model I will discuss these questions in light of the recent progress in the field focussing on our data that explain important aspects of substrate specificity and mechanism of rhomboids.