| Name | Peptidase family S41 (C-terminal processing peptidase family) |
|---|
| Family type peptidase | S41.001 - C-terminal processing peptidase-1 (Escherichia coli), MEROPS Accession MER0001295 (peptidase unit: 354-535) |
| Content of family | Peptidase family S41 contains serine endopeptidases. |
| History |
Identifier created: Proteolysis in Cell Function, pp13-21, IOS Press, Amsterdam (1997)
The family contains two very different subfamilies (see below). |
| Catalytic type | Serine |
| Active site | In the C-terminal processing peptidase, the active site consists of a Ser, Lys catalytic dyad (see the Alignments). In the tricorn core protein, the active site is the tetrad Ser745, His746, Ser965, Glu1023, which has been identified by co-crystallizing the peptidase with inhibitors (Brandsetter et al., 2001). Mutation studies show that both His746 and Ser965 are essential for activity, but in the crystal structures, only Ser965 interacted with the inhibitors. It has been suggested that His746 is ideally situated to activate Ser965, that Ser745 orientates the imidazolium ring of His746, and that Glu1023 is important for the formation of the oxyanion hole. The differences in the active sites between peptidases in the two subfamilies are striking, especially in that the order of catalytic residues in the sequence has evidently changed during evolution, which is unprecedented among peptidases within a single family. |
| Activities and specificities | The C-terminal processing peptidase recognizes a C-terminal tripeptide, Xaa-Yaa-Zaa, in which Xaa is preferably Ala or Leu, Yaa is preferably Ala or Tyr and Zaa is preferably Ala. Cleavage then occurs at a variable distance from the C-terminus. A typical cleavage is -Ala-Ala Arg-Ala-Ala-Lys-Glu-Asn-Tyr-Ala-Leu-Ala-Ala. The C-terminal carboxylate group is essential, and proteins with this group amidated are not substrates. The PDZ domain, which promotes protein-protein interactions, is important for substrate recognition.
The tricorn peptidase is thought to further degrade the peptides generated by the proteasome (T01.002). Substrates of both trypsin and chymotrypsin are cleaved. There are three tricorn-interacting factors, F1 (S33.005), F2 (M01.020) and F3 (M01.021), which associate with the tricorn complex; all three are aminopeptidases with differing specificities. |
| Inhibitors | The C-terminal processing peptidase is unaffected by typical inhibitors of serine, cysteine, metallo- or aspartic peptidases (Silber et al., 1992). The tricorn peptidase is inhibited by Tos-Phe-CH2Cl and Tos-Lys-CH2Cl, as well as a series of peptidyl-chloromethanes designed to probe the steric constraints of the active site (Brandstetter et al., 2001; Kim et al., 2002). The chloromethanes react with the active site Ser, not with the His, as would be expected in family S1, say. |
| Molecular structure | Tertiary structures have been determined for members of both subfamilies. The structure of C-terminal processing peptidase-2 from Scenedesmus obliquus shows that the peptidase exists as a monomer, and consists of three domains: a helix bundle, a PDZ-like domain and a catalytic domain. The active site lies at the interface of the three domains (Liao et al., 2000).
The crystal structure of the tricorn peptidase (Brandsetter et al., 2001) shows that it is a homohexamer, though each 720-kDa complex can self-associate into an enormous icosahedral capsid structure containing twenty copies of the complex. Each tricorn peptidase monomer consists of five structural domains: a six-bladed beta-propeller, a seven-bladed beta-propeller, the two domains (C1 and C2) that carry the active site residues, and a PDZ-like domain between the C1 and C2 domains. The active site residues are distributed between the C1 and C2 domains, with Ser and His on C1 and Ser and Glu on C2. The two beta-propellers limit access to the active site. The beta-propeller domain of prolyl oligopeptidase (S09.001) also limits access of substrates to the active site, and in both peptidases the PDZ-like domain has been proposed to be important for substrate recognition. Only the nucleophilic serine is in an equivalent position between both structures, despite the fact that the C1, PDZ and C2 domains are conserved and no sequence rearrangement has occurred within these three domains. The domains that carry the active sites are each similar in structure to the clp endopeptidase (S14.001), and family S41 is included in clan SK. |
| Clan | SK |
| Basis of clan assignment | Protein fold of the peptidase unit for members of this family resembles that of endopeptidase Clp, the type example for clan SK. |
| Biological functions | The bacterial C-terminal processing peptidase-1 (S41.001) is believed to be important for the degradation of incorrectly synthesized proteins. Proteins synthesized from damaged mRNA are tagged with the tripeptide Leu-Ala-Ala at the C-terminus, which is the target for degradation by the C-terminal processing peptidase.
In the plant chloroplast, the precursor of the D1 protein of photosystem II is processed by C-terminal processing peptidase-2 (S41.002). Processing is essential for the light-driven assembly of the tetranuclear manganese cluster, and the new C-terminal Ala of the D1 protein ligates the manganese cluster either directly or indirectly. It is the manganese cluster that is responsible for photosynthetic oxidation of water, the source of electrons for the biosynthesis of organic compounds.
In archaea and bacteria, the proteasome and tricorn complexes provide a proteolytic pathway in which cytoplasmic proteins are degraded to amino acids. |
| Reviews | Reviews are available on the Tsp peptidase (S41.001) (Keiler & Sauer, 2004), the C-terminal processing peptidase (S41.002) (Inagaki & Satoh, 2004) and the tricorn core peptidase (S41.005, S41.006) (Tamura & Baumeister, 2004). |
| Statistics for family S41 | Sequences: | 14449 |
| Identifiers: | 20 |
| Identifiers with PDB entries: | 8 |
| Downloadable files |
Sequence library (FastA format) |
| Sequence alignment (FastA format) |
| Phylogenetic tree (Newick format) |
| Peptidases and Homologues |
MEROPS ID |
Structure |
| C-terminal processing peptidase-1 | S41.001 | Yes |
| C-terminal processing peptidase-2 | S41.002 | Yes |
| C-terminal processing peptidase-3 | S41.004 | - |
| ctpB peptidase | S41.007 | Yes |
| CtpA peptidase (Synechocystis-type) | S41.008 | - |
| CtpB peptidase | S41.009 | - |
| CtpC peptidase | S41.010 | - |
| Pep putative peptidase (Vibrio-type) | S41.012 | Yes |
| CtpA peptidase (Borrelia-type) | S41.013 | - |
| interphotoreceptor retinoid-binding protein unit 1 | S41.950 | - |
| interphotoreceptor retinoid-binding protein unit 2 | S41.951 | Yes |
| interphotoreceptor retinoid-binding protein unit 1 (Mus-type) | S41.952 | - |
| interphotoreceptor retinoid-binding protein unit 2 (Mus-type) | S41.953 | - |
| interphotoreceptor retinoid-binding protein unit 3 (Bos taurus) and similar | S41.954 | - |
| MAGUK p55 subfamily member | S41.956 | - |
| At3g57680 (Arabidopsis thaliana) | S41.A01 | - |
| At5g46390 (Arabidopsis thaliana)-type peptidase | S41.A02 | - |
| Subfamily S41A non-peptidase homologues | non-peptidase homologue | Yes |
| Subfamily S41A unassigned peptidases | unassigned | - |
