The domain within your query sequence starts at position 114 and ends at position 332; the E-value for the Pept_C1 domain shown below is 2.28e-112.

Some of the required catalytic sites were not detected in this domain. It is probably inactive! Check the literature (PubMed 20480081 ) for details.

Catalytic residues
PositionAmino acidPresent?


Papain family cysteine protease
SMART accession number:SM00645
Description: -
Interpro abstract (IPR000668):

This group of proteins belong to the cysteine peptidase family C1, sub-family C1A (papain family, clan CA).

The papain family has a wide variety of activities, including broad-range (papain) and narrow-range endo-peptidases, aminopeptidases, carboxypeptidases, dipeptidyl peptidases and enzymes with both exo- and endo-peptidase activity [ (PUBMED:7845226) ]. Members of the papain family are widespread, found in bacteria, archaea, fungi, and practically all protozoa, plants and mammals [ (PUBMED:7845226) ], and some viruses such as baculoviruses [ (PUBMED:1363350) ]. The proteins are typically lysosomal or secreted. The catalytic residues of papain are Cys-25 and His-159, other important residues being Gln-19, which helps form the 'oxyanion hole', and Asn-175, which orientates the imidazole ring of His-159. Most papain-like cysteine peptidases are irreversibly inhibited by the synthetic inhibitor E64 [ (PUBMED:7044372) ]. Leupeptin is a reversible inhibitor but is also an inhibitor of chymotrypsin-like serine peptidases.

A papain-like cysteine proteinase is typically synthesised as an inactive precursor (or zymogen) with an N-terminal propeptide. Activation requires removal of the propeptide. The propeptide is required for the proper folding of the newly synthesised enzyme, maintaining the peptidase in an inactive state and stabilisation of the enzyme against denaturing at neutral to alkaline pH conditions. Amino acid residues within the pro-region mediate their membrane association, and play a role in the transport of the proenzyme to lysosomes. A propeptide can exhibit high selectivity for inhibition of the peptidase from which it originates [ (PUBMED:12188906) ].

The subfamily includes the following well characterised peptidases:

  • Animal lysosomal peptidases such as cathepsins B (EC, L (EC, H (EC, S (EC, K (EC, F (EC, O (EC, V (EC and X (a carboxypeptidase, EC
  • Plant peptidases such as papain (EC, ficin (EC, chymopapain (EC, asclepain A (EC, actinidin (EC, glycyl endopeptidase (EC, caricain (EC, ananain (EC, stem bromelain (EC and fruit bromelain (EC
  • Protozoan peptidases such as histolysain (EC and cruzipain (EC
  • Viral peptidases such as V-cath (EC

There are also proteins in the family that are not peptidases because one or more of the active site residues is not conserved. These include testin, tubulointerstitial nephritis antigen and silicatein.

Cysteine peptidases with a chymotrypsin-like fold are included in clan PA, which also includes serine peptidases. Cysteine peptidases that are N-terminal nucleophile hydrolases are included in clan PB. Cysteine peptidases with a tertiary structure similar to that of the serine-type aspartyl dipeptidase are included in clan PC. Cysteine peptidases with an intein-like fold are included in clan PD, which also includes asparagine lyases.

A cysteine peptidase is a proteolytic enzyme that hydrolyses a peptide bond using the thiol group of a cysteine residue as a nucleophile. Hydrolysis involves usually a catalytic triad consisting of the thiol group of the cysteine, the imidazolium ring of a histidine, and a third residue, usually asparagine or aspartic acid, to orientate and activate the imidazolium ring. In only one family of cysteine peptidases, is the role of the general base assigned to a residue other than a histidine: in peptidases from family C89 (acid ceramidase) an arginine is the general base. Cysteine peptidases can be grouped into fourteen different clans, with members of each clan possessing a tertiary fold unique to the clan. Four clans of cysteine peptidases share structural similarities with serine and threonine peptidases and asparagine lyases. From sequence similarities, cysteine peptidases can be clustered into over 80 different families [ (PUBMED:11517925) ]. Clans CF, CM, CN, CO, CP and PD contain only one family.

Cysteine peptidases are often active at acidic pH and are therefore confined to acidic environments, such as the animal lysosome or plant vacuole. Cysteine peptidases can be endopeptidases, aminopeptidases, carboxypeptidases, dipeptidyl-peptidases or omega-peptidases. They are inhibited by thiol chelators such as iodoacetate, iodoacetic acid, N -ethylmaleimide or p -chloromercuribenzoate.

Clan CA includes proteins with a papain-like fold. There is a catalytic triad which occurs in the order: Cys/His/Asn (or Asp). A fourth residue, usually Gln, is important for stabilising the acyl intermediate that forms during catalysis, and this precedes the active site Cys. The fold consists of two subdomains with the active site between them. One subdomain consists of a bundle of helices, with the catalytic Cys at the end of one of them, and the other subdomain is a beta-barrel with the active site His and Asn (or Asp). There are over thirty families in the clan, and tertiary structures have been solved for members of most of these. Peptidases in clan CA are usually sensitive to the small molecule inhibitor E64, which is ineffective against peptidases from other clans of cysteine peptidases [ (PUBMED:7044372) ].

Clan CD includes proteins with a caspase-like fold. Proteins in the clan have an alpha/beta/alpha sandwich structure. There is a catalytic dyad which occurs in the order His/Cys. The active site His occurs in a His-Gly motif and the active site Cys occurs in an Ala-Cys motif; both motifs are preceded by a block of hydrophobic residues [ (PUBMED:9891971) ]. Specificity is predominantly directed towards residues that occupy the S1 binding pocket, so that caspases cleave aspartyl bonds, legumains cleave asparaginyl bonds, and gingipains cleave lysyl or arginyl bonds.

Clan CE includes proteins with an adenain-like fold. The fold consists of two subdomains with the active site between them. One domain is a bundle of helices, and the other a beta barrell. The subdomains are in the opposite order to those found in peptidases from clan CA, and this is reflected in the order of active site residues: His/Asn/Gln/Cys. This has prompted speculation that proteins in clans CA and CE are related, and that members of one clan are derived from a circular permutation of the structure of the other.

Clan CL includes proteins with a sortase B-like fold. Peptidases in the clan hydrolyse and transfer bacterial cell wall peptides. The fold shows a closed beta barrel decorated with helices with the active site at one end of the barrel [ (PUBMED:14725770) ]. The active site consists of a His/Cys catalytic dyad.

GO process:proteolysis (GO:0006508)
GO function:cysteine-type peptidase activity (GO:0008234)
Family alignment:
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There are 19688 Pept_C1 domains in 19347 proteins in SMART's nrdb database.

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