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

• Published in: The EMBO journal 2001-12, Vol.20 (23), p.6570-6582
• Main Authors: Turk, Dušan, Janjić, Vojko, Štern, Igor, Podobnik, Marjetka, Lamba, Doriano, Dahl, Søren Weis, Lauritzen, Connie, Pedersen, John, Turk, Vito, Turk, Boris
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; apoptosis; Baculoviridae - metabolism; Binding Sites; Cathepsin C - chemistry; Cathepsin C - genetics; Cell Line; cysteine protease; Dimerization; Endopeptidases - chemistry; granzyme; Haim- Munk syndrome; Humans; inflammation; Insecta; Models, Molecular; Molecular Sequence Data; Mutation, Missense; Papillon-Lefevre Disease - genetics; Papillon-Lefevre Disease - metabolism; Papillon-Lefevre syndrome; Protein Conformation; Protein Folding; Protein Structure, Tertiary; Proteinase inhibitors; Recombinant Proteins - chemistry; Sequence Homology, Amino Acid; Serine Endopeptidases - chemistry; Substrate Specificity; Syndrome; zymogen activation
• ISSN: 0261-4189; 1460-2075; 1460-2075
• DOI: 10.1093/emboj/20.23.6570

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 domain transforms the framework of a papain‐like endopeptidase into a robust oligomeric protease‐processing enzyme. The tetrahedral arrangement of the active sites exposed to solvent allows approach of proteins in their native state; the massive body of the exclusion domain fastened within the tetrahedral framework excludes approach of a polypeptide chain apart from its termini; 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 originates from a metallo‐protease inhibitor. The location of missense mutations, characterized in people suffering from Haim–Munk and Papillon–Lefevre syndromes, suggests how they disrupt the fold and function of the enzyme.