Intramembrane proteases (IMPRs) cleave transmembrane proteins inside the lipid bilayer. They regulate a growing number of biological processes, and our knowledge about the evolutionary and functional niches these unusual enzymes have filled is slowly unravelling. Although structures of representative members of four IMPR families have been solved, the mechanism of substrate recognition and cleavage is still poorly understood. Here I offer a view on substrate recognition by IMPRs from the angle of their biological functions. Zooming in on rhomboid proteases I delineate the emerging principles and areas of contention, and argue that by studying the mechanisms, specificity and natural substrate repertoires of IMPRs we can understand the properties for which they have been selected in evolution.

Institute of Organic Chemistry and Biochemistry Academy of Sciences of the Czech Republic Prague Czech Republic

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