Catalysis of serine oligopeptidases is controlled by a gating filter mechanism

Proteases have a variety of strategies for selecting substrates in order to prevent uncontrolled protein degradation. A recent crystal structure deter mination of prolyl oligopeptidase has suggested a way for substrate selecti on involving an unclosed seven-bladed beta -propeller domain. We have engin eered a disulfide bond between the first and seventh blades of the propelle r, which resulted in the loss of enzymatic activity. These results provided direct evidence for a novel strategy of regulation in which oscillating pr opeller blades act as a gating filter during catalysis, letting small pepti de substrates into the active site while excluding large proteins to preven t accidental proteolysis.