| Name | Peptidase family S54 (Rhomboid family) |
|---|
| Family type peptidase | S54.001 - rhomboid-1 (Diptera) (Drosophila melanogaster), MEROPS Accession MER0015449 (peptidase unit: 101-355) |
| Content of family | Family S54 contains membrane-bound serine endopeptidases. |
| History |
Identifier created: MEROPS 5.7 (17 December 2001)
The protein Rhomboid has been known to be important for embryo development in Drosophila melanogaster for many years, but was only shown to be a peptidase by Urban et al. in 2001 (Urban et al., 2001). Subsequently, the precursors of cell-signalling factors were shown to be substrates (for a review see Brown & Pascall, 2004. The family is widely distributed amongst bacteria, archaea and eukaryotes. |
| Catalytic type | Serine |
| Active site residues | S217 H281 |
| Active site | From the tertiary structure of the GlpG protein from Escherichia coli, a catalytic dyad only exists, with the catalytic serine in the fourth and the catalytic histidine in the sixth transmembrane domain ((Wang et al., 2006); see the Alignment). A catalytic triad had previously been identified by site-directed mutagenesis (Urban et al., 2001), but the asparagine third member is not within bonding distance of the histidine. Similarly, the existence of an oxyanion hole is not confirmed. Two residues on the partially buried loop have been shown to be essential for activity by site-directed mutagenesis (Urban et al., 2001) and are proposed to be important for the gating function of this loop. |
| Activities and specificities | Spitz protein, a substrate of Rhomboid, is membrane-bound with a single transmembrane domain in the middle of the protein. There is a C-terminal cytoplasmic domain and an N-terminal lumenal domain which is homologous to the epidermal growth-factor. Although the exact cleavage site has not been determined, it is known that Spitz is cleaved within the transmembrane domain and that a region of the lumenal domain (residues 140-144, Glu-Lys-Ala-Ser-Ile) is the substrate-recognition site (Urban & Freeman, 2003). |
| Inhibitors | TPCK and 3,4-DCI have been shown to inhibit processing of the Spitz protein (Urban et al., 2001). |
| Molecular structure | The tertiary structure from the GlpG protein from Escherichia coli has been determined (Wang et al., 2006). The GlpG protein has six transmembrane domains (other members of the family are predicted to have seven), with the N- and C-terminal ends anchored in the cytoplasm. One transmembrane domain is shorter than the rest, creating an internal, aqueous cavity just below the membrane surface and it is here were proteolysis occurs. There is also a membrane-embedded loop between the first and second transmembrane domains which is postulated to act as a gate controlling substrate access to the active site. No other family of serine peptidases is known to have active site residues within transmembrane domains (although transmembrane active sites are known for aspartic peptidase and metallopeptidases), and the GlpG protein has the type structure for clan ST. |
| Clan | ST |
| Basis of clan assignment | Active site residues occur in the order S, H in the sequence. |
| Biological functions | Rhomboid-1 acts at two different stages during the development of the Drosophila embryo. Early on, it is required to establish position along the dorsoventral axis. Later, it is required to specify the fate of neuronal precursor cells (Bier et al., 1990). It cleaves the transmembrane proteins Spitz, Gurken and Keren within their transmembrane domains to release a soluble TGFalpha-like growth factor. Cleavage occurs in the Golgi, following translocation of the substrates from the endoplasmic reticulum membrane by Star, another transmembrane protein. The growth factors are then able to activate the epidermal growth factor receptor (Urban et al., 2002).
Few substrates of mammalian rhomboid homologues have been determined, but rhomboid-like protein 2 (S54.002) has been shown to cleave ephrin B3 (Pascall & Brown, 2004.
The AarA protein (S54.004) is thought to activate a factor that regulates gene expression in response to changes in the population size of the bacterium Providencia stuartii (Rather et al., 1999), but can also activate the Spitz protein (Gallio et al., 2002).
In Saccharomyces cerevisiae the Pcp1 protein (S54.007) has a completely different function, and is a mitochondrial endopeptidase required for the activation of cytochrome c peroxidase and for the processing of the mitochondrial dynamin-like protein Mgm1 (Esser et al., 2002; Herlan et al., 2003). The peroxidase is nuclearly-encoded and has to be first processed by mAAA (XM41-001) to remove a targeting signal. |
| Reviews | Reviews have been written by Brown & Pascall (2004) and Dutt et al. (2004). |
| Statistics for family S54 | Sequences: | 13499 |
| Identifiers: | 53 |
| Identifiers with PDB entries: | 3 |
| Downloadable files |
Sequence library (FastA format) |
| Sequence alignment (FastA format) |
| Phylogenetic tree (Newick format) |
| Peptidases and Homologues |
MEROPS ID |
Structure |
| rhomboid-1 (Diptera) | S54.001 | - |
| rhomboid-like protein 2 | S54.002 | - |
| AarA peptidase | S54.004 | - |
| rhomboid-like protein 1 | S54.005 | - |
| rhomboid like 3 peptidase (Homo sapiens) | S54.006 | - |
| Pcp1 peptidase (yeast) | S54.007 | - |
| rhomboid-like protein 5 | S54.008 | - |
| PARL peptidase | S54.009 | - |
| rhomboid-2 (Drosophila-type) | S54.010 | - |
| rhomboid-3 | S54.011 | - |
| rhomboid-4 (insect) | S54.012 | - |
| ROM-1 peptidase | S54.013 | - |
| rhomboid YqgP peptidase | S54.014 | - |
| RBL2 peptidase | S54.015 | - |
| GlpG peptidase (Escherichia-type) | S54.016 | Yes |
| ROM4 peptidase (Plasmodium-type) | S54.017 | - |
| ROM1 peptidase (Plasmodium-type) | S54.018 | - |
| ROM1 peptidase (Toxoplasma-type) | S54.019 | - |
| ROM2 peptidase (Toxoplasma-type) | S54.020 | - |
| ROM3 peptidase (Toxoplasma-type) | S54.021 | - |
| ROM4 peptidase (Toxoplasma-type) | S54.022 | - |
| ROM5 peptidase (Toxoplasma-type) | S54.023 | - |
| GlpG peptidase (Haemophilus-type) | S54.024 | Yes |
| At5g25752 rhomboid peptidase | S54.025 | - |
| EhROM1 peptidase (Entamoeba histolytica) | S54.026 | - |
| RhoII peptidase (Haloferax volcanii) and similar | S54.027 | - |
| rhomboid peptidase (Pseudomonas sp.) | S54.028 | - |
| rhomboid peptidase 2 (Mycobacterium sp.) | S54.029 | - |
| GlpG g.p. (Shigella sonnei) | S54.030 | - |
| RHBDD3 g.p. (Homo sapiens) | S54.951 | - |
| iRhom1 | S54.952 | - |
| iRhom2 | S54.953 | - |
| rhomboid-like protein 5 | S54.954 | - |
| rhomboid domain containing 2 | S54.955 | - |
| At1g52580 (Arabidopsis thaliana) | S54.A01 | - |
| At5g07250 (Arabidopsis thaliana) | S54.A02 | - |
| At4g23070 (Arabidopsis thaliana) | S54.A03 | - |
| At1g12750 (Arabidopsis thaliana) | S54.A04 | - |
| At2g29050 (Arabidopsis thaliana) | S54.A05 | - |
| At3g53780 (Arabidopsis thaliana) | S54.A06 | - |
| At1g18600 (Arabidopsis thaliana) | S54.A07 | - |
| At1g25290 (Arabidopsis thaliana) | S54.A08 | - |
| rho-6 (Drosophila melanogaster) | S54.A09 | - |
| rom-4 g.p. (Caenorhabditis elegans) | S54.A10 | - |
| rom-3 g.p. (Caenorhabditis elegans) | S54.A11 | - |
| Cg8972 protein | S54.A12 | - |
| ROM8 g.p. (Plasmodium falciparum) | S54.A13 | - |
| SPBC30D10.19c g.p. (Schizosaccharomyces pombe) | S54.A14 | - |
| Rbd2 g.p. (Schizosaccharomyces pombe) | S54.A15 | - |
| DDB_G0295849 g.p. (Dictyostelium discoideum) | S54.A16 | - |
| DDB_G0275611 g.p. (Dictyostelium discoideum) | S54.A17 | - |
| ydcA g.p. (Bacillus subtilis) | S54.A18 | - |
| PF1228 g.p. (Pyrococcus furiosus) | S54.A19 | - |
| Family S54 non-peptidase homologues | non-peptidase homologue | - |
| Family S54 unassigned peptidases | unassigned | Yes |
