Structural determinants of regulated proteolysis in pathogenic bacteria by ClpP and the proteasome

•As in eukaryotes, chambered proteases are essential for normal physiology in bacteria.•The timing and selection of specific substrates for degradation is incompletely understood.•Structural studies have revealed interactions between proteases and activators, providing new insight into how degradation might be regulated. Bacteria use gated proteolytic machines for routine protein quality control and regulated responses to environmental conditions. This review discusses recent advances in understanding the structure and regulation of ClpP proteases, nanomachines widely distributed across bacteria, and the bacterial proteasome, a protease found in relatively few species. For both machines, activators confer substrate specificity. We highlight new data from organisms encoding two ClpP isoforms and the central role of activators as platforms for integrating regulatory signals. Because proteolytic systems contribute to survival and virulence of many bacterial pathogens, understanding their forms and functions enables new approaches to design targeted therapeutics.