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Intramembrane rhomboid proteases are of particular interest because of theirfunction to hydrolyze a peptide bond of a substrate buried in the membrane.Crystal structures of the bacterial rhomboid protease GlpG have revealed acatalytic dyad (Ser201-His254) and oxyanion hole (His150/Asn154/the backboneamide of Ser201) surrounded by the protein matrix and contacting a narrow waterchannel. Although multiple crystal structures have been solved, the catalyticmechanism of GlpG is not completely understood. Because it is a serine protease,hydrogen bonding interactions between the active site residues are thought toplay a critical role in the catalytic cycle. Here, we dissect the interactionenergies among the active site residues His254, Ser201, and Asn154 ofEscherichia coli  GlpG, which form a hydrogen bondingnetwork. We combine double mutant cycle analysis with stability measurementsusing steric trapping. In mild detergent, the active site residues are weaklycoupled with interaction energies(ΔΔ G  Inter ) of ‒1.4 kcal/molbetween His254 and Ser201 and ‒0.2 kcal/mol between Ser201 and Asn154.Further, by analyzing the propagation of single mutations of the active siteresidues, we find that these residues are important not only for function butalso for the folding cooperativity of GlpG. The weak interaction between Ser andHis in the catalytic dyad may partly explain the unusually slow proteolysis byGlpG compared with other canonical serine proteases. Our result suggests thatthe weak hydrogen bonds in the active site are sufficient to carry out theproteolytic function of rhomboid proteases.

The rhomboid protease GlpG has weak interaction energies in its active site hydrogen bond network