When we have food intake, pH of the stomach reaches around 1. This highly acidic environment is indispensable for the digestion. Gastric proton pump, H⁺,K⁺-ATPase is a membrane protein responsible for the gastric acid secretion. Its crystal structures now reveal how this proton pump extrudes H⁺ even into the pH 1 environment of the stomach.

Intramembrane-cleaving proteases (I-CLiPs) are a unique class of proteases, which catalyze proteolysis of target membrane proteins within the lipid bilayer. I-CLiPs are found in all kingdoms of life and are involved in various cellular processes such as stress responses, lipid homeostasis, induction of apoptosis and bacterial virulence. RseP, an Escherichia coli I-CLiP, plays a critical role in the extracytoplasmic stress response essential for bacterial survival. In this review, I will summarize the results of our recent studies on the structure and function of RseP and propose a model of the substrate recognition and cleavage by this peculiar protease.