| Clan type peptidase | C01.001 - papain (Carica papaya), MEROPS Accession MER0000647 (peptidase unit: 134-345); PDB accession 1PE6 |
| History | Biochem.J. 290:205-218 (1993) |
| Description | Cysteine nucleophile; catalytic residues in the order Cys, His, Asn (or Asp) in sequence |
| Contents of clan | Clan CA contains several families of cysteine peptidases. |
| Evidence | Clan CA contains all the families of peptidases that are known to have structures similar to that of papain. Other families are assigned to clan CA on the basis of sequence motifs. In addition to the residues Cys158 and His292 of the catalytic dyad, two other functionally important residues are commonly present in papain and its relatives (see the Alignment). These are Gln152 that helps in the formation of the ‘oxyanion hole’, an electrophilic centre that stabilizes the tetrahedral intermediate, and Asn308 (sometimes Asp in families C12, C19, C28 and C39), which is thought to orientate the imidazolium ring of the catalytic His (Polgar, 2004). The order of these residues in the sequence is Gln, Cys, His, Asn/Asp, and in mature papain, the numbering is Gln19, Cys25, His159 and Asn175. Clan CN also contains peptidases with a Cys, His catalytic dyad but with a different fold. There are several families of peptidases that process polyproteins from RNA viruses that also possess a Cys, His catalytic dyad, but cannot at present be assigned to either clan CA or CN. |
| Catalytic mechanism | Catalysis by the clan CA peptidases proceeds through an acyl enzyme intermediate. The roles of His159, Gln19 and Asn175 have been fully reviewed by Polgar (2004). |
| Peptidase activity | Most of the peptidases in clan CA are endopeptidases, but several peptidases in family C1 have predominantly exopeptidase activities (see the family C1 summary). The clan contains a number of families of polyprotein-processing peptidases of RNA viruses, including family C28, which contains the foot-and-mouth disease virus L-peptidase. |
| Protein fold | Structures have been determined for several families in the clan: C1 (papain, Kamphuis etal, 1984), C2 (Hosfield et al., 1999), C10 (Kagawa et al., 2000), C12 (Johnston et al., 1997), C19 (Hu et al., 2002), C28 (Guarne et al., 1998), C47 (Filipek et al., 2003), C54 (Sugawara et al., 2005), C58 (Zhu et al., 2004) and C66 (Wenig et al., 2004). The fold consists of two domains with the active site between them. One domain consists of a bundle of helices, with the active site Cys at the end of one of them; the second domain is a beta barrel and carries the active site His and Asn (or Asp). |
| Evolution | It is very possible that clan CA shares an origin with clan CE, the characteristic folds being related by circular permutation, as is suggested in the SCOP database [sunid 54001]. The sequences of each of the type peptidases (papain, C01.001, and adenain, C05.001) of the two clans contain two sequence motifs that are generally conserved throughout the clans. These motifs contain the key catalytic residues, Cys and His, and are Gln-(Xaa)n1-Cys and His-(Xaa)n2-Asn/Glu (where n1 = 5 or 6 and n2 = 15 or 16), respectively. In clan CA the Cys-motif occurs first in the sequence, followed by the His, whereas the reverse is the case in clan CE. The idea that the two parts of the catalytic site have exchanged positions in a circular permutation during the evolution of the clans is consistent with the protein folds, as can be seen in the three-dimensional and two-dimensional representations of the structures in the MEROPS database. |
| Homologous non-peptidase families | Non-peptidase proteins that are homologous with the clan CA peptidases include phytochelatin synthase (Vivares et al., 2005), arylamine N-acetyltransferase (Boukouvala & Fakis, 2005) and coagulation factor XIII transglutaminase (Makarova et al., 1999). |
| Activation mechanism | Papain and many other members of subfamily C1A are synthesized as inactive proenzymes with N-terminal propeptides. In the example of cathepsin B (C01.060) the propeptide blocks access of substrate to the already formed active site (Podobnik et al., 1997). The propeptides are cleaved (often autolytically) to generate the active peptidases. The free propeptides of cathepsins B, L and others remain potent inhibitors of the peptidases (Guay et al., 2000), and with homologues they form family I29. In family C10, the proenzyme of streptopain is also autolytically activated (Chen et al., 2003). In family C2, some calpains are activated by a Ca2+-induced conformational change (Strobl et al., 2000). |
|
Other databases
| PFAM | CL0125 |
|
| SCOP | 54001 |
| C1 |
papain (Carica papaya) |
Yes |
| C2 |
calpain-2 (Homo sapiens) |
Yes |
| C6 |
potato virus Y-type helper component peptidase (potato virus Y) |
Yes |
| C10 |
streptopain (Streptococcus pyogenes) |
Yes |
| C10 |
agglutinin peptidase ({Marasmius oreades}) (Marasmius oreades) |
- |
| C11 |
OTULIN peptidase (Homo sapiens) |
- |
| C12 |
GtgE peptidase (Salmonella enterica) |
- |
| C13 |
HopX1 peptidase ({Pseudomonas syringae)} (Pseudomonas syringae) |
- |
| C14 |
PlyC phage lysin (Streptococcus phage C1) |
- |
| C15 |
papain-like peptidase 1 alpha (simian hemorrhagic fever virus) (simian hemorrhagic fever virus) |
- |
| C110 |
kyphoscoliosis peptidase (Mus musculus) |
- |
| C111 |
coagulation factor XIIIa (Homo sapiens) |
- |
| C113 |
IgdE peptidase ({Streptococcus suis}) (Streptococcus suis) |
- |
| C115 |
MINDY-1 protein (Homo sapiens) |
- |
| C117 |
SpvD g.p. ({Salmonella enterica}) (Salmonella typhimurium) |
- |
| C119 |
LotA g.p. ({Legionella pneumophila}) (Legionella pneumophila) |
- |
| C12 |
ubiquitinyl hydrolase-L1 (Homo sapiens) |
Yes |
| C121 |
MINDY-4 peptidase (Homo sapiens) |
- |
| C124 |
Lem27 ({Legionella pneumophila}) (Legionella pneumophila) |
- |
| C16 |
murine hepatitis coronavirus papain-like peptidase 1 (murine hepatitis virus) |
Yes |
| C19 |
ubiquitin-specific peptidase 14 (Homo sapiens) |
Yes |
| C21 |
tymovirus peptidase (turnip yellow mosaic virus) |
- |
| C28 |
foot-and-mouth disease virus L-peptidase (foot-and-mouth disease virus) |
Yes |
| C31 |
porcine reproductive and respiratory syndrome arterivirus-type cysteine peptidase alpha (lactate-dehydrogenase-elevating virus) |
Yes |
| C32 |
equine arteritis virus-type cysteine peptidase (porcine reproductive and respiratory syndrome virus) |
Yes |
| C33 |
equine arteritis virus Nsp2-type cysteine peptidase (equine arteritis virus) |
- |
| C39 |
bacteriocin-processing peptidase (Pediococcus acidilactici) |
Yes |
| C47 |
staphopain A (Staphylococcus aureus) |
Yes |
| C51 |
D-alanyl-glycyl peptidase (staphylococcal phage phi11-type) (Staphylococcus aureus) |
- |
| C54 |
autophagin-1 (Homo sapiens) |
Yes |
| C58 |
YopT peptidase (Yersinia pestis) |
Yes |
| C64 |
Cezanne peptidase (Homo sapiens) |
- |
| C65 |
otubain-1 (Homo sapiens) |
Yes |
| C66 |
IdeS peptidase (Streptococcus pyogenes) |
Yes |
| C67 |
CylD peptidase (Homo sapiens) |
- |
| C70 |
AvrRpt2 peptidase (Pseudomonas syringae) |
- |
| C71 |
pseudomurein endoisopeptidase Pei (Methanobacterium phage psiM2) |
- |
| C76 |
viral tegument protein deubiquitinylating peptidase (human herpesvirus 1) |
- |
| C78 |
UfSP1 peptidase (Mus musculus) |
Yes |
| C83 |
gamma-glutamylcysteine dipeptidyltranspeptidase (Nostoc sp. PCC 7120) |
Yes |
| C85 |
OTUD5 peptidase ({Homo sapiens}) (Homo sapiens) |
Yes |
| C86 |
ataxin-3 (Homo sapiens) |
- |
| C87 |
nairovirus deubiquitinylating peptidase (Crimean-Congo hemorrhagic fever virus) |
Yes |
| C93 |
LapG peptidase ({Pseudomonas fluorescens}) (Pseudomonas fluorescens) |
Yes |
| C96 |
McjB peptidase (Escherichia coli) |
- |
| C98 |
USPL1 peptidase (Homo sapiens) |
- |
