Cell membranes are sites of interface between the cell and the outside world, and constitute major sites of signaling. Membranes also form the front lines where deadly pathogens first contact human cells and initiate infection. Our main focus is a family of membrane-immersed enzymes, termed rhomboid proteases, which catalyze a biochemical reaction that cuts protein segments within the membrane. This cleavage liberates proteins from the membrane, either to activate signals rapidly, or to inactivate other targets. Because of its versatility this basic biochemical reaction has evolved to control many cellular processes in all forms of life, from diverse bacteria to humans. But how these enzymes achieve catalysis within the membrane, and their roles in all but a few organisms, remain unclear.
We study the biochemical principles governing how rhomboid enzymes catalyze reactions immersed within the membrane. We have reconstituted rhomboid activity with pure components, and are using a combination of membrane biophysics, cell biology and chemical genetics to probe their mechanism. We have also focused on rhomboid function in deadly human pathogens, and discovered that rhomboid enzymes execute an array of essential functions: malaria and related parasites use their rhomboid enzymes to invade human cells, while a parasitic ameba uses its rhomboid in phagocytosis and immune evasion. Targeting rhomboid enzymes may be a way of treating multiple infectious diseases.