Family M48
Summary for family M48
| Name | Peptidase family M48 (Ste24 endopeptidase family) |
|---|
| Family type peptidase | M48.001 - Ste24 peptidase (Saccharomyces cerevisiae), MEROPS Accession MER0002635 (peptidase unit: 162-453) |
| Content of family | Peptidase family M48 contains metalloendopeptidases. |
| History |
Identifier created: Handbook of Proteolytic Enzyme, Academic Press, London (1998)
Mating in yeast involves two pheromones, designated the a- and alpha-mating factors. Each is secreted by a different haploid cell type, which then fuse to form a diploid cell. Processing of the a-mating factor from its precursor involves three proteolytic processing events performed by prenyl peptidase 2 (G05.001), Ste24 endopeptidase (M48.001) and Axl1 peptidase (M16.007). Homologues have been found in animals, plants and bacteria. |
| Catalytic type | Metallo |
| Active site | Peptidases in family M48 contain a single catalytic zinc ion tetrahedrally co-ordinated by two histidines within an HEXXH motif, an as yet undetermined third residue and water. The glutamate within the HEXXH motif is assumed to be a catalytic residue. Site-directed mutagenesis of the His and Glu residues within the HEXXH motif of Ste24 endopeptidase has confirmed that these are essential for catalysis (Fujimura-Kamada et al., 1997). |
| Activities and specificities | Eukaryotic peptidases from family M48 have a requirement for substrates that are prenylated at a C-terminal motif known as CAAX, in which A is an aliphatic residue, and the lipid is attached to the cysteine residue. Ste24 endopeptidase is important for the processing of the yeast a-mating factor precursor. Two cleavages are performed: release of a C-terminal tetrapeptide (cleavage occurring at a farnesylated Cys residue, Boyartchuk et al., 1997) followed by release of the first of two N-terminal peptides (Fujimura-Kamada et al., 1997). Although the biological function of human farnesylated-protein converting enzyme 1 (M48.003) is unknown, it is capable of processing the yeast a-mating factor precursor (Schmidt et al., 2000). Homologues from eukaryotes other than yeast probably have broader substrate specificities: the homologue from Arabidopsis thaliana has been shown to cleave several prenylated proteins (Bracha et al., 2002). |
| Inhibitors | The metal chelator 1,10-phenanthroline has been shown to inhibit Ste24 endopeptidase (Tam et al., 2001). |
| Molecular structure | The Ste24 endopeptidase is an integral membrane protein with seven transmembrane domains. It resides in the membrane of the endoplasmic reticulum, with the N-terminus in the lumen and the active site and the C-terminus in the cytoplasm (Tam et al., 2001). The HEXXH motif is extracellular but adjacent to a transmembrane domain and therefore close to the membrane surface. The Oma1 endopeptidase (M48.018) is located within the mitochondrial inner membrane (Kaser et al., 2003). |
| Clan | MA |
| Subclan | MA(E) |
| Basis of clan assignment | Family M48 is included in clan MA on the basis of comparisons of hidden Markov models derived from the MEROPS family alignments |
| Biological functions | Ste24 endopeptidase is essential for mating in Saccharomyces, but it is not essential for viability (Fujimura-Kamada et al., 1997). Without Ste24 endopeptidase, the a-mating factor precursor is not completely processed in the MATa haploid cell type. Human farnesylated-protein converting enzyme 1 may be important for processing prelamin A, a farnesylated protein that is cleaved twice. In cells with a defective peptidase gene, incompletely processed prelamin A accumulates in the nuclear envelope (Pendas et al., 2002). Farnesylated-protein converting enzyme 1 performs the second processing step for prelamin A, releasing a fifteen-residue peptide containing the prenylated C-terminal Cys (Bergo et al., 2002; Pendas et al., 2002). The Oma1 endopeptidase is believed to degrade misfolded membrane proteins, thereby helping to maintain the integrity of the mitochondrial inner membrane (Kaser et al., 2003). In bacteria, the HtpX endopeptidase is induced by heat shock and may be involved in the degradation of abnormal proteins because these accumulate in htpX mutants (Kornitzer et al., 1991. |
| Pharmaceutical and biotech relevance | Deficiencies in lamin A, a component of the nuclear lamina, lead to abnormalities in the nuclear architecture, and knockouts of farnesylated-protein converting enzyme 1 in mice cause growth retardation, muscular dystrophy and premature death (Pendas et al., 2002; Bergo et al., 2002). |
| Statistics for family M48 | Sequences: | 12122 |
| Identifiers: | 24 |
| Identifiers with PDB entries: | 5 |
| Downloadable files |
Sequence library (FastA format) |
| Sequence alignment (FastA format) |
| Phylogenetic tree (Newick format) |
| Peptidases and Homologues |
MEROPS ID |
Structure |
| Ste24 peptidase | M48.001 | Yes |
| farnesylated-protein converting enzyme 1 | M48.003 | Yes |
| Mername-AA052 peptidase | M48.008 | - |
| YhfN peptidase | M48.009 | - |
| STE24 peptidase (Sarcomastigophora-type) | M48.020 | - |
| CG9002 g.p. (Drosophila melanogaster) | M48.A05 | - |
| CG9001 g.p. (Drosophila melanogaster) | M48.A06 | - |
| DDB_G0270268 g.p. (Dictyostelium discoideum) | M48.A07 | - |
| zmpste24 g.p. (Dictyostelium discoideum-type) | M48.A08 | - |
| Subfamily M48A non-peptidase homologues | non-peptidase homologue | - |
| Subfamily M48A unassigned peptidases | unassigned | - |
| Peptidases and Homologues |
MEROPS ID |
Structure |
| metalloprotease-related protein-1 | M48.017 | - |
| Oma1 peptidase | M48.018 | - |
| GSU1437 putative peptidase | M48.019 | Yes |
| low osmolarity induced peptidase | M48.022 | - |
| BepA (Escherichia coli) | M48.023 | Yes |
| At5g51740 (Arabidopsis thaliana)-type peptidase | M48.A01 | - |
| YcaL protein (Escherichia coli) | M48.A03 | - |
| Subfamily M48C non-peptidase homologues | non-peptidase homologue | - |
| Subfamily M48C unassigned peptidases | unassigned | - |
|
Peptidases not assigned to subfamily
|
| Peptidases and Homologues |
MEROPS ID |
Structure |
| PetP peptidase (Synechocystis) | M48.024 | - |
| DDB_G0286165 g.p. (Dictyostelium discoideum) | M48.A09 | - |
| Family M48 non-peptidase homologues | non-peptidase homologue | - |
| Family M48 unassigned peptidases | unassigned | - |
