Premium
Structure of human dipeptidyl peptidase I (cathepsin C): exclusion domain added to an endopeptidase framework creates the machine for activation of granular serine proteases
Author(s) -
Turk Dušan,
Janjić Vojko,
Štern Igor,
Podobnik Marjetka,
Lamba Doriano,
Dahl Søren Weis,
Lauritzen Connie,
Pedersen John,
Turk Vito,
Turk Boris
Publication year - 2001
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/20.23.6570
Subject(s) - proteases , endopeptidase , library science , cathepsin , philosophy , biology , biochemistry , computer science , enzyme
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.