Intramembrane proteolysis: principles of substrate recognition and membrane protein fate

Intramembrane proteases catalyze peptide bond hydrolysis within cellular membranes, regulating processes including signaling, protein quality control, and membrane protein turnover. Recent advances in cryo-electron microscopy, biochemistry, and molecular dynamics simulations have transformed our understanding of how these enzymes recognize and process substrates within the lipid bilayer. Here, we discuss how dynamic interactions among proteases, substrates, and membranes govern substrate recognition. Structural and biophysical studies reveal how conformational dynamics, membrane remodeling, and specific protease-substrate interactions enable processing of membrane-embedded substrates. Studies of rhomboid pseudoproteases further suggest that transmembrane-domain recognition represents a conserved principle of membrane protein processing that extends beyond proteolysis itself. Finally, we consider how recognition determines membrane protein fate, linking protease activity to signaling, proteostasis, and nonproteolytic scaffolding functions.