| Name | Peptidase family T1 (proteasome family) |
|---|
| Family type peptidase | T01.002 - archaean proteasome, beta component (Thermoplasma acidophilum), MEROPS Accession MER0000548 (peptidase unit: 9-211) |
| Content of family | Peptidase family T1 contains the component peptidases of the proteasome and related compound peptidases. |
| History |
Identifier created: Proteolysis in Cell Function, pp13-21, IOS Press, Amsterdam (1997)
The discovery of a fifth peptidase catalytic type came when the crystallographic structure of the proteasome (T01.002) from Thermoplasma acidophylum was determined (Lowe et al., 1995), showing an N-terminal threonine at the active site. The catalytic type of the proteasome had been a puzzle because of its resistence to inhibition by most standard peptidase inhibitors. The structure of the 20S proteasome from Saccharomyces cerevisiae (##XT01.001##; Groll et al., 1997) revealed the number of subunits in the peptidase complex as fourteen, and the N-terminal threonine residues of some of the subunits as catalytic residues. Prokaryote homologues have a simpler structure: the bacterial proteasome (T01.005) has four different kinds of subunits, the archaean (T01.002) only two, and the bacterial HslVU (T01.006) peptidase consists of a proteasome subunit (HslV) and an ATP-binding subunit (HslU). |
| Catalytic type | Threonine |
| Active site | The N-terminal threonine residues of some of the beta subunits are the nucleophiles in catalysis (Seemuller et al., 1995). |
| Activities and specificities | The eukaryotic proteasome has three different activities (trypsin-like, chymotrypsin-like and cleavage after glutamate). Each activity resides in a different β subunit. The archaean and bacterial proteasomes have only chymotrypsin-like activity. The catalytic subunits are synthesized as precursors that are autocatalytically activated. The synthetic substrate Suc-Leu-Leu-Val-Tyr-NHMec has been used to assay the chymotrysin-like activity, various trypsin substrates for the trypsin-like activity and Z-Leu-Leu-Glu-NHNap for the peptidylglutamate activity. |
| Inhibitors | No known natural protein inhibitors are known. The small, naturally occurring compounds lactacystin , epoxomycin and eponemycin from actinomycete bacteria inactivate by interaction with the catalytic threonine, blocking all three catalytic activities. Chymostatin inhibits the chymotrypsin-like activity and leupeptin the trypsin-like. |
| Molecular structure | The proteasome complex molecule consists of four rings of seven subunits, and takes the form of a hollow cylinder with the active sites on the walls of the inner chamber. Rings one and four contain alpha-type subunits whereas rings two and three are composed of beta-type subunits. In the eukaryotic proteasome, the only subunits with peptidase activity are three of the seven kinds of beta subunits, although in mammals three additional active subunits inducible by gamma-interferon can replace the constitutive active subunits. Each subunit is the product of a different gene. Additional kinds of subunits may be added as a cap to the proteasome (the 19S cap). The uncapped enzyme is known as the 20S proteasome (20S being its approximate sedimentation coefficient; ##XT01.001##) whereas the capped enzyme is the 26S proteasome (##XT01.002##). The cap consists of several subunits, one of which is a deubiquitinating enzyme in peptidase family M67 (M67.002). In bacteria such as Rhodococcus, the proteasome consists of two different alpha subunits and two different, active beta subunits. In archaea, there is only one alpha and one beta subunit gene, though the number of components and rings in the proteasome is the same as in eukaryotes. The bacterial proteasome is different again with a single active peptidase subunit and an unrelated ATP-binding subunit. In all forms of the proteasome, the peptidase subunits are N-terminal nucleophile hydrolases, which means that in the mature protein the catalytic residue is Thr1. The N-terminal threonine possesses both the nucleophile (the hydroxyl group) and the general base (the amino group) and can be artificially replaced with serine without significant loss of activity. The tertiary structure shows an alpha/beta/beta/alpha sandwich, with each beta sheet containing four strands and with the active site at one end of the beta sheet. The structure is similar to those of other Ntn hydrolases in clan PB, such as penicillin acylase (S45.001) and glycosylasparaginase (T02.001). |
| Clan | PB |
| Subclan | PB(T) |
| Basis of clan assignment | Type family of clan PB. |
| Peptidases and Homologues |
MEROPS ID |
Structure |
| archaean proteasome, beta component | T01.002 | Yes |
| bacterial proteasome, beta component | T01.005 | Yes |
| proteasome subunit beta1c | T01.010 | Yes |
| proteasome subunit beta2c | T01.011 | Yes |
| proteasome subunit beta5c | T01.012 | Yes |
| proteasome subunit beta1i | T01.013 | Yes |
| proteasome subunit beta2i | T01.014 | Yes |
| proteasome subunit beta5i | T01.015 | Yes |
| proteasome subunit beta5t | T01.016 | - |
| protein serine kinase c17 | T01.017 | Yes |
| similar to proteasome subunit beta type 6 (Rattus norvegicus) | T01.019 | - |
| similar to proteasome subunit beta type 6 (Rattus norvegicus) (but not T01.019) | T01.020 | Yes |
| archaean proteasome, alpha subunit | T01.970 | Yes |
| proteasome subunit alpha 6 | T01.971 | Yes |
| proteasome subunit alpha 2 | T01.972 | Yes |
| proteasome subunit alpha 4 | T01.973 | Yes |
| proteasome subunit alpha 7 | T01.974 | Yes |
| proteasome subunit alpha 5 | T01.975 | Yes |
| proteasome subunit alpha 1 | T01.976 | Yes |
| proteasome subunit alpha 3 | T01.977 | Yes |
| 2410072d24rik protein (mouse) | T01.978 | - |
| bacterial proteasome, alpha subunit | T01.980 | - |
| similar to proteasome subunit beta type 3 (Rattus norvegicus) | T01.982 | - |
| proteasome subunit beta 3 | T01.983 | Yes |
| proteasome subunit beta 2 | T01.984 | Yes |
| similar to proteasome subunit beta type 3 (Rattus norvegicus) (but not T01.982) | T01.985 | - |
| proteasome subunit beta 1 | T01.986 | Yes |
| proteasome subunit beta 4 | T01.987 | Yes |
| similar to proteasome subunit beta 3 (Mus musculus) | T01.989 | - |
| similar to splicing factor U2AF homolog (Mus musculus) | T01.990 | Yes |
| Mername-AA230 peptidase homologue (Homo sapiens) | T01.991 | - |
| Mername-AA241 peptidase homologue (Mus musculus) | T01.994 | - |
| Mername-AA242 peptidase homologue (Mus musculus) | T01.995 | - |
| Mername-AA243 peptidase homologue | T01.996 | - |
| Mername-AA244 peptidase homologue | T01.997 | Yes |
| protein similar to proteasome subunit iota | T01.998 | - |
| similar to proteasome subunit alpha type 2 (Rattus norvegicus) | T01.999 | - |
| yip3 (Drosophila melanogaster) | T01.A01 | - |
| proteasome subunit beta2 (Drosophila melanogaster) | T01.A02 | Yes |
| CG12161 protein (Drosophila melanogaster) | T01.A03 | - |
| CG18341 protein (Drosophila melanogaster) | T01.A04 | - |
| CG31742 protein (Drosophila melanogaster) | T01.A05 | - |
| beta5 subunit (Drosophila melanogaster) | T01.A06 | - |
| CG9868 protein (Drosophila melanogaster) | T01.A07 | - |
| pbs-5 g.p. (Caenorhabditis elegans) | T01.A09 | - |
| PBE2 g.p. (Arabidopsis thaliana) | T01.A10 | - |
| 20S proteasome component beta 6 | T01.A12 | Yes |
| PFE0915c g.p. (Plasmodium falciparum) | T01.A14 | Yes |
| PF10_0111 g.p. (Plasmodium falciparum) | T01.A15 | Yes |
| proteasome subunit beta pseudogene | T01.P01 | - |
| Mername-AA231 pseudogene (Homo sapiens) | T01.P02 | - |
| Mername-AA232 pseudogene (Homo sapiens) | T01.P03 | - |
| Subfamily T1A non-peptidase homologues | non-peptidase homologue | Yes |
| Subfamily T1A unassigned peptidases | unassigned | Yes |
