Biophysical mechanism of rhomboid proteolysis: Setting a foundation for therapeutics

Rhomboid proteolysis is an important cellular process that involves cleavage of transmembrane substrates by membrane-embedded rhomboid proteases. Such proteases can cleave substrates with essential roles in the cell, and their action has been implicated in human diseases. The remarkable sensitivity of rhomboid proteolysis to the lipid membrane environment highlights the usefulness of rhomboid proteases as model systems to dissect the role of lipids in reaction mechanisms of membrane proteins, including cleavage of substrates by γ-secretase. I discuss here the hydrogen-bond networks likely important for the reaction mechanism of rhomboid proteases, and how the composition of the lipid membrane can alter protein dynamics.