| Name | Peptidase family S26 (signal peptidase I family) |
|---|
| Family type peptidase | S26.001 - signal peptidase I (Escherichia coli), MEROPS Accession MER0000589 (peptidase unit: 78-324) |
| Content of family | Peptidase family S26 contains endopeptidases. |
| History |
Identifier created: Methods Enzymol. 244:19-61 (1994)
Milstein et al. (1972) recognised the existence of a peptidase that was involved in the processing of newly-synthesised immunoglobulin molecules, removing an N-terminal peptide. The peptide came to be called the signal, or leader peptide, and the class of enzymes that remove it are signal peptidases, most of which are in peptidase family S26. The bacterial signal peptidase was discovered by Chang et al. (1978). The signal peptidases for years resisted identification as serine peptidases, because their catalytic mechanism is quite unlike those of the better-known serine peptidases such as chymotrypsin (clan PA) and subtilisin (clan SB) for which the inhibitors that were thought to be diagnostic for serine peptidases had been optimised. The fact that signal peptidase I (S26.001) is a serine peptidase eventually became clear with the work of Black (1993).
The signal peptide system is of dominant importance in the secretion of proteins by eukaryotic cells, and is also important in bacteria, but bacteria have other systems also, some involving signal peptidase II (A08.001) or type 4 prepilin peptidase (A24.001). |
| Catalytic type | Serine |
| Active site | The active site residues take the form of a catalytic dyad that is Ser, Lys in subfamily S26A; the Ser is the nucleophile in catalysis, and the Lys is the general base. Evidence about the mechanism comes from crystal structures, mutagenesis and chemical modifications, reviewed by Paetzel and co-workers (Paetzel & Strynadka, 1999, Paetzel et al., 2000).
In subfamily S26B, the catalytic dyad is Ser, His, as was pointed out for the mammalian endoplasmic reticulum enzyme (S26.009, S26.010) by VanValkenburgh et al. (1999). The Ser, His dyad of Bacillus subtilis SipW was described by Tjalsma et al. (2000). There are also conserved Asp residues that appear to contribute to activity in family S26 (Sung & Dalbey, 1992; VanValkenburgh et al., 1999), and two isoleucine residues contribute to substrate specificity (Karla et al., 2004). |
| Activities and specificities | The function of most peptidases in family S26 is the processing of newly-synthesised secreted proteins. They remove the hydrophobic, N-terminal signal peptides as the proteins are translocated across membranes. Despite having no distinct consensus sequence other than a frequent 'Ala-Xaa-Ala' motif preceding the cleavage site, signal peptidases cleave signal sequences with high fidelity (Carlos et al., 2000). The specificities of the enzymes have been analysed in detail (Nielsen et al., 1997). An atypical member of the family is the TraF peptidase (S26.014) which has the remarkable activity of producing a cyclic protein of the Pseudomonas pilin system (Kalkum et al., 2004). |
| Inhibitors | Inhibitors of the signal peptidase I include lipopeptides such as arylomycin (Paetzel et al., 2004), as well as substituted beta-lactams (e.g. (5S,6S)-6-[(R)-acetoxyethyl]-penem-3-carboxylate: Lammertyn et al., 2004). |
| Molecular structure | The signal peptidases are membrane proteins. The bacterial signal peptidase I, which is the most intensively studied, has two N-terminal transmembrane segments and a hydrophilic, C-terminal catalytic region that is naturally located in the periplasmic space. Crystal structures have been determined for the C-terminal, catalytic domain both with and without bound inhibitors (Paetzel et al., 1998; Paetzel et al., 2002).
Although the bacterial signal peptidase I is monomeric, signal peptidases of eukaryotic cells commonly function as oligomeric complexes containing two divergent copies of the catalytic monomer. These are the Imp1 and Imp2 signal peptidases of the mitochondrial inner membrane (S26.002 and S26.012, respectively). The 18-kDa and 21-kDa components (S26.009, S26.010) of the endoplasmic reticulum signal peptidase in mammals are associated with unrelated subunits also. |
| Clan | SF |
| Basis of clan assignment | Protein fold of the peptidase unit for members of this family resembles that of represor LexA, the type example of clan SF. |
| Biological functions | The use of signal peptides to direct newly synthesised proteins to a secretory pathway is common to all three domains of living organisms, and the peptidases of family S26 are the major enzymes that remove the signal peptides and facilitate secretion. In E. coli the signal peptidase is inserted in the plasma membrane, and the catalytic domain is in the periplasmic space (Dalbey, 2004). In inner-membrane signal peptidases of eukaryotic mitochondria and chloroplasts process proteins that are destined for the inter-membrane spaces of the organelles (Packer & Howe, 2004). |
| Pharmaceutical and biotech relevance | The bacterial signal peptidases of subfamily S26A are required for the viability of many bacteria and are therefore regarded as drug targets (Paetzel et al., 2000). |
| Statistics for family S26 | Sequences: | 19747 |
| Identifiers: | 34 |
| Identifiers with PDB entries: | 4 |
| Downloadable files |
Sequence library (FastA format) |
| Sequence alignment (FastA format) |
| Phylogenetic tree (Newick format) |
| Peptidases and Homologues |
MEROPS ID |
Structure |
| signal peptidase I | S26.001 | Yes |
| mitochondrial inner membrane peptidase 1 | S26.002 | - |
| signal peptidase SipS | S26.003 | - |
| signal peptidase SipT | S26.004 | - |
| signal peptidase SipU | S26.005 | - |
| signal peptidase SipV | S26.006 | - |
| signal peptidase SipP | S26.007 | - |
| thylakoidal processing peptidase | S26.008 | - |
| mitochondrial inner membrane peptidase 2 | S26.012 | - |
| Streptococcus-type signal peptidase | S26.015 | - |
| SpsB signal peptidase | S26.016 | Yes |
| SipM signal peptidase | S26.018 | - |
| similar to type-I signal peptidase | S26.019 | - |
| similar to type-I signal peptidase | S26.020 | - |
| similar to type-I signal peptidase | S26.021 | - |
| signal peptidase (Mycobacterium tuberculosis-type) | S26.024 | - |
| signal peptidase sipX | S26.025 | - |
| PA1303 peptidase (Pseudomonas sp.) | S26.026 | - |
| At1g06870 (Arabidopsis thaliana) | S26.A01 | - |
| Plsp1 peptidase (Arabidopsis thaliana) | S26.A02 | - |
| At1g29960 (Arabidopsis thaliana) | S26.A05 | - |
| At1g23470 (Arabidopsis thaliana) | S26.A06 | - |
| T3F20.15 protein (Arabidopsis thaliana) | S26.A08 | - |
| CG11110 protein (Drosophila melanogaster) | S26.A09 | - |
| Subfamily S26A non-peptidase homologues | non-peptidase homologue | - |
| Subfamily S26A unassigned peptidases | unassigned | Yes |
| Peptidases and Homologues |
MEROPS ID |
Structure |
| signalase (animal) 18 kDa component | S26.009 | - |
| signalase (animal) 21 kDa component | S26.010 | - |
| signal peptidase SipW (Bacillus-type) | S26.011 | - |
| archaean signal peptidase (Euryarchaeota) | S26.017 | - |
| Mername-AA228 putative signal peptidase | S26.022 | - |
| signal peptidase (invertebrate) | S26.023 | - |
| At3g15710 (Arabidopsis thaliana) | S26.A03 | - |
| At1g52600 (Arabidopsis thaliana)-type peptidase | S26.A04 | - |
| PF0326 g.p. (Pyrococcus furiosus) | S26.A11 | - |
| Subfamily S26B non-peptidase homologues | non-peptidase homologue | - |
| Subfamily S26B unassigned peptidases | unassigned | - |
