Peptidase C1A subfamily (MEROPS database nomenclature); composed of cysteine peptidases (CPs) similar to papain, including the mammalian CPs (cathepsins B, C, F, H, L, K, O, S, V, X and W). Papain is an endopeptidase with specific substrate preferences, primarily for bulky hydrophobic or aromatic residues at the S2 subsite, a hydrophobic pocket in papain that accommodates the P2 sidechain of the substrate (the second residue away from the scissile bond). Most members of the papain subfamily are endopeptidases. Some exceptions to this rule can be explained by specific details of the catalytic domains like the occluding loop in cathepsin B which confers an additional carboxydipeptidyl activity and the mini-chain of cathepsin H resulting in an N-terminal exopeptidase activity. Papain-like CPs have different functions in various organisms. Plant CPs are used to mobilize storage proteins in seeds. Parasitic CPs act extracellularly to help invade tissues and cells, to hatch or to evade the host immune system. Mammalian CPs are primarily lysosomal enzymes with the exception of cathepsin W, which is retained in the endoplasmic reticulum. They are responsible for protein degradation in the lysosome. Papain-like CPs are synthesized as inactive proenzymes with N-terminal propeptide regions, which are removed upon activation. In addition to its inhibitory role, the propeptide is required for proper folding of the newly synthesized enzyme and its stabilization in denaturing pH conditions. Residues within the propeptide region also play a role in the transport of the proenzyme to lysosomes or acidified vesicles. Also included in this subfamily are proteins classified as non-peptidase homologs, which lack peptidase activity or have missing active site residues.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|...
gi 4138250    1 TLDGKDYWLVKNSWGLNFGDQGYIRMARnNKNHCGIASYCSYP 43
Cdd:cd02248 169 TENGVDYWIVKNSWGTSWGEKGYIRIAR-GSNLCGIASYASYP 210

cysteine proteinase; Provisional

                         10        20        30
                 ....*....|....*....|....*....|....*...
gi 4138250     4 GKDYWLVKNSWGLNFGDQGYIRMARNNK--NHCGIASY 39
Cdd:PTZ00200 402 KKRYWIIKNSWGTDWGENGYMRLERTNEgtDKCGILTV 439

Peptidase C1A subfamily (MEROPS database nomenclature); composed of cysteine peptidases (CPs) similar to papain, including the mammalian CPs (cathepsins B, C, F, H, L, K, O, S, V, X and W). Papain is an endopeptidase with specific substrate preferences, primarily for bulky hydrophobic or aromatic residues at the S2 subsite, a hydrophobic pocket in papain that accommodates the P2 sidechain of the substrate (the second residue away from the scissile bond). Most members of the papain subfamily are endopeptidases. Some exceptions to this rule can be explained by specific details of the catalytic domains like the occluding loop in cathepsin B which confers an additional carboxydipeptidyl activity and the mini-chain of cathepsin H resulting in an N-terminal exopeptidase activity. Papain-like CPs have different functions in various organisms. Plant CPs are used to mobilize storage proteins in seeds. Parasitic CPs act extracellularly to help invade tissues and cells, to hatch or to evade the host immune system. Mammalian CPs are primarily lysosomal enzymes with the exception of cathepsin W, which is retained in the endoplasmic reticulum. They are responsible for protein degradation in the lysosome. Papain-like CPs are synthesized as inactive proenzymes with N-terminal propeptide regions, which are removed upon activation. In addition to its inhibitory role, the propeptide is required for proper folding of the newly synthesized enzyme and its stabilization in denaturing pH conditions. Residues within the propeptide region also play a role in the transport of the proenzyme to lysosomes or acidified vesicles. Also included in this subfamily are proteins classified as non-peptidase homologs, which lack peptidase activity or have missing active site residues.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|...
gi 4138250    1 TLDGKDYWLVKNSWGLNFGDQGYIRMARnNKNHCGIASYCSYP 43
Cdd:cd02248 169 TENGVDYWIVKNSWGTSWGEKGYIRIAR-GSNLCGIASYASYP 210

Cathepsin B group; composed of cathepsin B and similar proteins, including tubulointerstitial nephritis antigen (TIN-Ag). Cathepsin B is a lysosomal papain-like cysteine peptidase which is expressed in all tissues and functions primarily as an exopeptidase through its carboxydipeptidyl activity. Together with other cathepsins, it is involved in the degradation of proteins, proenzyme activation, Ag processing, metabolism and apoptosis. Cathepsin B has been implicated in a number of human diseases such as cancer, rheumatoid arthritis, osteoporosis and Alzheimer's disease. The unique carboxydipeptidyl activity of cathepsin B is attributed to the presence of an occluding loop in its active site which favors the binding of the C-termini of substrate proteins. Some members of this group do not possess the occluding loop. TIN-Ag is an extracellular matrix basement protein which was originally identified as a target Ag involved in anti-tubular basement membrane antibody-mediated interstitial nephritis. It plays a role in renal tubulogenesis and is defective in hereditary tubulointerstitial disorders. TIN-Ag is exclusively expressed in kidney tissues.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|
gi 4138250    1 TLDGKDYWLVKNSWGLNFGDQGYIRMARnNKNHCGIASYC 40
Cdd:cd02620 195 VENGVPYWLAANSWGTDWGENGYFRILR-GSNECGIESEV 233

Cathepsin C; also known as Dipeptidyl Peptidase I (DPPI), an atypical papain-like cysteine peptidase with chloride dependency and dipeptidyl aminopeptidase activity, resulting from its tetrameric structure which limits substrate access. Each subunit of the tetramer is composed of three peptides: the heavy and light chains, which together adopts the papain fold and forms the catalytic domain; and the residual propeptide region, which forms a beta barrel and points towards the substrate's N-terminus. The subunit composition is the result of the unique characteristic of procathepsin C maturation involving the cleavage of the catalytic domain and the non-autocatalytic excision of an activation peptide within its propeptide region. By removing N-terminal dipeptide extensions, cathepsin C activates granule serine peptidases (granzymes) involved in cell-mediated apoptosis, inflammation and tissue remodelling. Loss-of-function mutations in cathepsin C are associated with Papillon-Lefevre and Haim-Munk syndromes, rare diseases characterized by hyperkeratosis and early-onset periodontitis. Cathepsin C is widely expressed in many tissues with high levels in lung, kidney and placenta. It is also highly expressed in cytotoxic lymphocytes and mature myeloid cells.

                        10        20        30
                ....*....|....*....|....*....|....*.
gi 4138250    4 GKDYWLVKNSWGLNFGDQGYIRMARnNKNHCGIASY 39
Cdd:cd02621 202 GEKYWIVKNSWGSSWGEKGYFKIRR-GTNECGIESQ 236

cathepsin C-like protein; Provisional

                         10        20        30
                 ....*....|....*....|....*....|....*....
gi 4138250     2 LDGK--DYWLVKNSWGLNFGDQGYIRMARnNKNHCGIAS 38
Cdd:PTZ00049 632 INGKlyKYWIGRNSWGKNWGKEGYFKIIR-GKNFSGIES 669

Serine-repeat antigen protein; Provisional

                          10        20        30
                  ....*....|....*....|....*....|
gi 4138250      5 KDYWLVKNSWGLNFGDQGYIRMARNNKNHC 34
Cdd:PTZ00462  741 KSYWIVRNSWGKYWGDEGYFKVDMYGPSHC 770

Cysteine protease, C1A family [Posttranslational modification, protein turnover, chaperones];

                        10        20
                ....*....|....*....|..
gi 4138250    5 KDYWLVKNSWGLNFGDQGYIRM 26
Cdd:COG4870 190 DGAFIIKNSWGTGWGDNGYFWI 211

Peptidase C1B subfamily (MEROPS database nomenclature); composed of eukaryotic bleomycin hydrolases (BH) and bacterial aminopeptidases C (pepC). The proteins of this subfamily contain a large insert relative to the C1A peptidase (papain) subfamily. BH is a cysteine peptidase that detoxifies bleomycin by hydrolysis of an amide group. It acts as a carboxypeptidase on its C-terminus to convert itself into an aminopeptidase and peptide ligase. BH is found in all tissues in mammals as well as in many other eukaryotes. Bleomycin, a glycopeptide derived from the fungus Streptomyces verticullus, is an effective anticancer drug due to its ability to induce DNA strand breaks. Human BH is the major cause of tumor cell resistance to bleomycin chemotherapy, and is also genetically linked to Alzheimer's disease. In addition to its peptidase activity, the yeast BH (Gal6) binds DNA and acts as a repressor in the Gal4 regulatory system. BH forms a hexameric ring barrel structure with the active sites imbedded in the central channel. The bacterial homolog of BH, called pepC, is a cysteine aminopeptidase possessing broad specificity. Although its crystal structure has not been solved, biochemical analysis shows that pepC also forms a hexamer.

                        10
                ....*....|....*....
gi 4138250    8 WLVKNSWGLNFGDQGYIRM 26
Cdd:cd00585 378 WKVENSWGEKVGKKGYFVM 396