What lurks beneath (the membrane): a mechanistic exploration of rhomboid proteolysis

At the turn of the millennium an extraordinary class of enzymes that cut proteins inside the cell membrane was discovered. Rhomboid proteases are the largest family of these ancient membrane‐immersed enzymes. Although deceptively simple, the act of hydrolyzing a single peptide bond inside the water‐excluding environment of the cell membrane has evolved to trigger cell signaling events during bacterial growth and animal embryogenesis, as well as mitochondrial quality control throughout the life of a cell. The membrane is a challenging environment for catalysis. We have been pioneering new quantitative methods to study rhomboid catalysis directly inside the membrane and combining them with modern X‐ray crystallography approaches. I will discuss an integrated but unexpected model for how rhomboid proteases function, and the promising new opportunities that it raises for combating devastating parasitic diseases that have plagued mankind for millennia, including malaria. Support or Funding Information This work was supported by NIH grants 2R01AI066025 and R01AI110925, the Howard Hughes Medical Institute, and the David & Lucile Packard Foundation.