Structure of human dipeptidyl peptidase I (cathepsin C): exclusion domain added to an endopeptidase framework creates the machine for activation of granular serine proteases

Dipeptidyl peptidase I (DPPI) or cathepsin C is the physiological activator of groups of serine proteases from immune and inflammatory cells vital for defense of an organism. The structure presented shows how an additional do main transforms the framework of a papain-like endopeptidase into a robust oligomeric protease-processing enzyme. The tetrahedral arrangement of the a ctive sites exposed to solvent allows approach of proteins in their native state; the massive body of the exclusion domain fastened within the tetrahe dral framework excludes approach of a polypeptide chain apart from its term ini;, and the carboxylic group of Asp1 positions the N-terminal amino group of the substrate. Based on a structural comparison and interactions within the active site cleft, it is suggested that the exclusion domain originate s from a metallo-protease inhibitor. The location of missense mutations, ch aracterized in people suffering from Haim-Munk and Papillon-Lefevre syndrom es, suggests how they disrupt the fold and function of the enzyme.