Family M50
Summary for family M50
| Name | Peptidase family M50 (S2P protease family) |
|---|
| Family type peptidase | M50.001 - site 2 peptidase (Homo sapiens), MEROPS Accession MER0004458 (peptidase unit: 1-519) |
| Content of family | Peptidase family M50 contains metalloendopeptidases. |
| History |
Identifier created: MEROPS 3.03 (10 September 1998)
Two peptidases in family M50 have been characterised in detail: S2P peptidase (M50.001) and sporulation factor SpoIVFB (M50.002). They are quite dissimilar in sequence, and are the type peptidases of the separate subfamilies M50A and M50B, respectively. A second peptidase in subfamily M50A is the RseP peptidase of Escherichia coli (M50.004). All three proteins are thought to be largely embedded in cell membranes. |
| Catalytic type | Metallo |
| Active site | Family M50 peptidases contain an HEXXH motif. By analogy with other metallopeptidases it can be assumed that the glutamate has a catalytic role and the two histidines are ligands of a single zinc atom. Mutagenesis tends to support this, although it has been noted that both S2P peptidase and sporulation factor SpoIVFB retain significant activity when the putative catalytic Glu is replaced by Asp (Yu & Kroos, 2000). There is a more C-terminal Asp (in an invariant Asp-Gly motif) that is required for activity (Dong & Cutting, 2004) and which has been shown to be the third metal ligand in the tertiary structure of the MJ0392 protein (M50.006) from Methanocaldococcus jannaschii (Feng et al., 2007). In this structure the catalytic metal is zinc. |
| Activities and specificities | All the cleavages catalysed by peptidases in family M50 occur within, or very close to, membranes. S2P peptidase releases the N-terminal transcription factor domain from membrane-bound sterol regulatory element binding proteins (SREBPs), cleaving a Leu Cys bond in the first transmembrane helix of the substrate (Zelenski et al., 1999). Sporulation factor SpoIVFB (Bacillus subtilis) activates the factor sigmaK precursor by cleaving off a 20-residue propeptide (Green & Cutting, 2000). RseP peptidase (Escherichia coli) cleaves the anti-sigmaE protein RseA within a transmembrane segment (Akiyama et al., 2004). |
| Inhibitors | The protein BofA of Bacillus subtilis (I62.001) is a natural inhibitor of sporulation factor SpoIVFB (Zhou & Kroos, 2004). |
| Molecular structure | The tertiary structure has been determined for the MJ0392 protein (M50.006) from Methanocaldococcus jannaschii (Feng et al., 2007). Two of the metal ligands occur in an HEXXH motif, similar to that found in clan MA, and the third is an Asp. The active site is within one of the six transmembrane regions, and the fold is unlike that of thermolysin (M04.001). Accordingly, family M50 is placed in its own clan, MM. The peptidase occurs in an open and a closed conformation. In the closed conformation, the active site is surrounded by transmembrane helices and the substrate can not enter, though water molecules can gain access via a polar, central channel that opens on the cytoplasmic side. In the open conformation, helices 1 and 6 move apart by 10-12 angstroms, permitting entry of the substrate (Feng et al., 2007). |
| Clan | MM |
| Basis of clan assignment | Type family of clan MM. |
| Biological functions | The molecules of S2P peptidase, sporulation factor SpoIVFB and RseP peptidase are all extensively embedded in cell membranes, and the hydrophobicity even of the sequences containing the active site residues indicates that they cleave their substrates either within the membrane or very close to it. These peptidases are involved in the regulation of gene expression by proteolysis of transcription regulators. S2P peptidase, in the mammalian endoplasmic reticulum membrane, releases the N-terminal transcription factor domain from membrane-bound SREBPs, and the liberated domain then enters the nucleus and activates genes that control cholesterol uptake and synthesis (Zelenski et al., 1999). Sporulation factor SpoIVFB from Bacillus subtilis is involved in the later stages of the sporulation process, in which a peptidoglycan layer surrounds the protoplast. It activates the factor sigmaK precursor, and the active factor sigmaK then promotes attachment of an RNA polymerase to a specific initiation site, and so acts like a transcription factor, upregulating several genes including that of the SpoIVFB endopeptidase. RseP peptidase also cleaves transmembrane sequences (Akiyama et al., 2004), and it now seems very likely that intramembrane proteolysis (reviewed by Weihofen & Martoglio, 2003) is a general activity of peptidases in family M50. |
| Reviews | Rawson (2004) |
| Statistics for family M50 | Sequences: | 9444 |
| Identifiers: | 20 |
| 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 |
| site 2 peptidase | M50.001 | - |
| dS2P peptidase (Drosophila melanogaster) | M50.007 | - |
| mbtps2 g.p. (Dictyostelium discoideum) | M50.A08 | - |
| zinc metallopeptidase (Bacillus subtilis) | M50.A11 | - |
| Subfamily M50A non-peptidase homologues | non-peptidase homologue | - |
| Subfamily M50A unassigned peptidases | unassigned | Yes |
| Peptidases and Homologues |
MEROPS ID |
Structure |
| sporulation factor SpoIVFB | M50.002 | - |
| AraSP peptidase (Arabidopsis-type) | M50.003 | - |
| RseP peptidase | M50.004 | Yes |
| protein Rv2869c (Mycobacterium tuberculosis)-type peptidase | M50.005 | - |
| MjS2P-type peptidase | M50.006 | Yes |
| Stp1 peptidase | M50.008 | - |
| At4g20310-like peptidase | M50.009 | - |
| PF0167 g.p. (Pyrococcus furiosus) | M50.010 | - |
| RasP peptidase (Bacillus subtilis) | M50.011 | - |
| EGY2 peptidase (Arabidopsis thaliana) | M50.A01 | - |
| EGY1 peptidase (Arabidopsis thaliana) | M50.A02 | - |
| PF0392 g.p. (Pyrococcus furiosus) | M50.A04 | - |
| ywhC g.p. (Bacillus subtilis) | M50.A05 | - |
| PF0457 g.p. (Pyrococcus furiosus) | M50.A07 | - |
| ARASP g.p. (Arabidopsis thaliana) | M50.A10 | - |
| Subfamily M50B non-peptidase homologues | non-peptidase homologue | - |
| Subfamily M50B unassigned peptidases | unassigned | Yes |
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Peptidases not assigned to subfamily
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