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

Abstract

Dipeptidyl peptidase I (DPPI) or cathepsin C is the physiological activator of groups of serine proteases from immune and in¯ammatory 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.

A Plasmodium falciparum Dipeptidyl Aminopeptidase I Participates in Vacuolar Hemoglobin Degradation

“…Over the entire sequence the two proteins share 30% identity and 45% similarity (excluding gap positions). Several residues known to be important for peptidase activity are conserved in DPAP1; they are Asp-28, which in cathepsin C is the N-terminal residue of the exclusion domain and blocks the substrate binding cleft beyond the P2 site (38,39), and Cys-398, His-624, and Asn-648, which form the cysteine protease catalytic triad (40). A tyrosine residue that binds a chloride ion in the crystal structures of rat and human cathepsin C (38, 39) is also conserved (Tyr-549).…”

Cathepsin Cs Are Key for the Intracellular Survival of the Protozoan Parasite, Toxoplasma gondii

“…1). Several residues known to be important for peptidase activity are conserved in TgCPCs: the Asp at the N terminus of the exclusion domain, which blocks the substrate binding cleft beyond the P2 site (7,8), and Cys, His, and Asn, which form the cysteine protease catalytic triad in the active site (7,11). A tyrosine residue that binds a chloride ion in the crystal structures of rat and human cathepsin C is also conserved (Tyr-549).…”

“…Cathepsin C (also known as dipeptidyl peptidase I, DPPI) is a unique member of the papain family of cysteine proteases that include cathepsins B, L, K, H, and S. In contrast to the endopeptidase activity of other papain family cathepsins, cathepsin C has primarily exopeptidase activity and sequentially removes dipeptides from the free N termini of proteins and peptides (7)(8)(9). Human cathepsin C plays a role in lysosomal degradation of peptides and also functions as a key enzyme in the activation of granule serine proteases in human and murine immune cells (7)(8)(9)(10)(11).…”

“…Human cathepsin C plays a role in lysosomal degradation of peptides and also functions as a key enzyme in the activation of granule serine proteases in human and murine immune cells (7)(8)(9)(10)(11). We recently char-acterized the T. gondii cathepsin B (toxopain-1 or TgCPB) 2 (12) and cathepsin L (TgCPL) proteases.…”

Neutrophilic Cathepsin C Is Maturated by a Multistep Proteolytic Process and Secreted by Activated Cells during Inflammatory Lung Diseases

“…Cathepsin C (CatC) 3 (EC 3.4.14.1), also known as dipeptidyl peptidase I, is a member of cysteine cathepsins, which are lysosomal proteases belonging to the C1 family of papain-like cysteine peptidases (1)(2)(3). Cysteine cathepsins are synthetized as proteolytically inactive zymogens bearing a N-terminal removable propeptide (4,5).…”