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706  structures 1981  species 0  interactions 24463  sequences 703  architectures

Family: Peptidase_C1 (PF00112)

Summary: Papain family cysteine protease

Pfam includes annotations and additional family information from a range of different sources. These sources can be accessed via the tabs below.

This is the Wikipedia entry entitled "Cathepsin". More...

Cathepsin Edit Wikipedia article

A cathepsin is a type of protease, ie a type of protein that breaks apart other proteins. Cathepsins are present in all types of cells, from hepatocytes to neurons, and in many species including all animals.

Cathepsin actually refers to a family of proteases. There are approximately a dozen members of this family, which are distinguished from each other by their structures as well as which target proteins they most like to cleave.

The earliest record of "cathepsin" found in PubMed is from the Journal of Biological Chemistry in 1949 (see article 1 below).

Maver and Grecco. The hydrolysis of nucleoproteins by cathepsins from calf thymus. JBC 181 (2): 853-60.

Cathepsins have been implicated in cancer (see article 2 below for review),stroke (article 3) and even Alzheimer's Disease.

1. Maver and Greco. The hydrolysis of nucleoproteins by cathepsins from calf thymus. J Biol Chem. 1949 Dec;181(2):853-60. 2. Nomura and Katunuma. Involvement of cathepsins in the invasion, metastasis and proliferation of cancer cells. J Med Invest. 2005 Feb;52(1-2):1-9. Review. 3. Lipton. Ischemic cell death in brain neurons. Physiol Rev. 1999 Oct;79(4):1431-568.

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This is the Wikipedia entry entitled "Cysteine protease". More...

Cysteine protease Edit Wikipedia article

Proteases are enzymes that degrade polypeptides. Cysteine proteases have a common catalytic mechanism that involves a nucleophilic cysteine thiol in a catalytic triad. The first step is deprotonation of the thiol by an adjacent amino acid with a basic side chain, usually a histidine residue. The next step is nucleophilic attack of the deprotonated cysteine's anionic sulfur on the peptide carbonyl carbon. In this step, an amine is released, the histidine residue is restored to its deprotonated form, and a thioester intermediate linking the new carboxy-terminus to the cysteine thiol is formed. The thioester bond is subsequently hydrolyzed to generate a carboxylic acid, while regenerating the free enzyme.

Examples of Cysteine Proteases

Protease Regulation

Proteases are usually synthesized as large precursor proteins called zymogens, such as the serine protease precursors tryspinogen and chymotrypsinogen, and the aspartic protease precursor pepsinogen. The protease is activated by removal of an inhibitory segment or protein. Activation occurs once the protease is delivered to a specific intracellular compartment (e.g. lysosome) or extracellular environment (e.g. stomach). This system prevents the cell that produces the protease from being damaged by it.
Protease inhibitors are usually proteins with domains that enter or block a protease active site to prevent substrate access. In competitive inhibition, the inhibitor binds to the active site, thus preventing enzyme-substrate interaction. In non-competitive inhibition, the inhibitor binds to an allosteric site, which alters the active site and makes it unaccessible to the subrate.

Examples of Protease Inhibitors

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This is the Wikipedia entry entitled "Papain". More...

Papain Edit Wikipedia article

Papain is a protease present in papaya which is useful in tenderizing meat and other proteins. Its utility is in breaking down the tough meat fibers and has been utilized for thousands of years in its native South America. It is sold as a component in powdered meat tenderizer available in most supermarkets.

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

Papain family cysteine protease Provide feedback

No Pfam abstract.

Internal database links

External database links

This tab holds annotation information from the InterPro database.

InterPro entry 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.

Gene Ontology

The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets and the UniProtKB sequence database. More...

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We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.

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You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

HMM logo

HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...


This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

Note: You can also download the data file for the tree.

Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: Prosite
Previous IDs: Cys-protease;
Type: Domain
Sequence Ontology: SO:0000417
Author: Sonnhammer ELL
Number in seed: 157
Number in full: 24463
Average length of the domain: 195.8 aa
Average identity of full alignment: 30 %
Average coverage of the sequence by the domain: 53.57 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 61295632 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 20.7 20.7
Trusted cut-off 20.7 20.7
Noise cut-off 20.6 20.6
Model length: 219
Family (HMM) version: 26
Download: download the raw HMM for this family

Species distribution

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Colour assignments

Archea Archea Eukaryota Eukaryota
Bacteria Bacteria Other sequences Other sequences
Viruses Viruses Unclassified Unclassified
Viroids Viroids Unclassified sequence Unclassified sequence


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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the adjacent tab. More...

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For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Peptidase_C1 domain has been found. There are 706 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.

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AlphaFold Structure Predictions

The list of proteins below match this family and have AlphaFold predicted structures. Click on the protein accession to view the predicted structure.

Protein Predicted structure External Information
A0A044RFT9 View 3D Structure Click here
A0A044RM09 View 3D Structure Click here
A0A044RVL0 View 3D Structure Click here
A0A044RWQ7 View 3D Structure Click here
A0A044S545 View 3D Structure Click here
A0A044SAQ1 View 3D Structure Click here
A0A044SU60 View 3D Structure Click here
A0A044SUF8 View 3D Structure Click here
A0A044TYP6 View 3D Structure Click here
A0A072UTP9 View 3D Structure Click here
A0A077YZI7 View 3D Structure Click here
A0A077Z0Q9 View 3D Structure Click here
A0A077Z0X8 View 3D Structure Click here
A0A077Z108 View 3D Structure Click here
A0A077Z381 View 3D Structure Click here
A0A077Z3H9 View 3D Structure Click here
A0A077Z4A9 View 3D Structure Click here
A0A077Z5F2 View 3D Structure Click here
A0A077ZDU9 View 3D Structure Click here
A0A077ZGN1 View 3D Structure Click here
A0A077ZGS3 View 3D Structure Click here
A0A077ZGY4 View 3D Structure Click here
A0A077ZHU2 View 3D Structure Click here
A0A077ZQQ9 View 3D Structure Click here
A0A0G2JX50 View 3D Structure Click here
A0A0G2KAE5 View 3D Structure Click here
A0A0G2L792 View 3D Structure Click here
A0A0H5S901 View 3D Structure Click here
A0A0J9XKB3 View 3D Structure Click here
A0A0J9Y464 View 3D Structure Click here
A0A0J9Y553 View 3D Structure Click here
A0A0K0DTI1 View 3D Structure Click here
A0A0K0DYH0 View 3D Structure Click here
A0A0K0DZU6 View 3D Structure Click here
A0A0K0E0S6 View 3D Structure Click here
A0A0K0E2U3 View 3D Structure Click here
A0A0K0E2U4 View 3D Structure Click here
A0A0K0EBM3 View 3D Structure Click here
A0A0K0ED15 View 3D Structure Click here
A0A0K0EDR3 View 3D Structure Click here