Family I39
Summary for family I39
| Name | Inhibitor family I39 (alpha2M family) |
|---|
| Family type peptidase | I39.001 - alpha-2-macroglobulin (Homo sapiens), MEROPS Accession MER0018468 (inhibitor unit: 24-1474) |
| Content of family | Inhibitor family I39 contains mammalian alpha2-macroglobulin and other large homologous proteins that interact with endopeptidases regardless of catalytic type. |
| History |
Identifier created: MEROPS 6.1 (10 January 2003)
Barrett & Starkey (1973) observed that human alpha2-macroglobulin undergoes a unique interaction with a very wide variety of endopeptidases. Complexes are formed in which the activity of the peptidase is severely inhibited with large molecule substrates, but scarcely inhibited at all with small substrates. It was suggested that the interaction is triggered by cleavage of a peptide bond in a particularly susceptible region of the macroglobulin molecule termed the 'bait region'. This cleavage results in a conformational change in which the endopeptidase molecule is entrapped within that of the macroglobulin. Subsequent studies have validated this proposal (e.g. Crews et al., 1987; Kolodziej et al., 2002). The conformational change that occurs in the trapping of a peptidase results in an increase in electrophoretic mobility through a gel medium, so that 'slow' (unreacted) and 'fast' (reacted) electrophoretic forms can be distinguished (Barrett et al., 1979). |
| Peptidases inhibited | Alpha2-macroglobulin and its homologues inhibit the majority of endopeptidases regardless of family or catalytic type (Barrett, 1981). Most of the endopeptidases that do not interact either have strict specificity that prevents them from cleaving any bond in the "bait region" of the inhibitor (e.g. Ikai et al., 1999), or are molecules that are too large to be effectively internalised by the macroglobulin. |
| Mechanism of inhibition | Cleavage of any bond in the bait region triggers a dramatic conformational change in the inhibitor that results in the enclosure of the attacking peptidase molecule within the macroglobulin molecule (Barrett, 1981). In the complex, access of substrate molecules to the peptidase is restricted in a molecular-size-dependent way, so that inhibition is almost complete with large substrates, but marginal with small ones. |
| Molecular structure | alpha2-Macroglobulin is a homotetramer, in which the monomer is about 180 kDa. The tetramer can be regarded as a dimer of dimers, and the dimers can be separated by mild reduction (Barrett et al., 1979). The structure of the tetramer has been deduced by analysis of electron microscopic data (Boisset et al., 1996; Kolodziej et al., 2002). |
| Clan | IL |
| Biological functions | In mammals, alpha2-macroglobulin functions as a broad-spectrum endopeptidase-binding molecule that mediates the clearance of endopeptidases from the plasma. The complexed forms of the molecule present receptor-binding sites that lead to the rapid removal of the complexes from the circulation. This being the case, the inhibition of activity of the bound peptidase may not always be crucial. The homologues of alpha2-macroglobulin act similarly in invertebrate animals (e.g. Armstrong et al., 1996). alpha2-Macroglobulin can be thought of as part of the system for defence against bacterial infection because its very wide specificity of interaction with endopeptidases is likely to include those used by pathogens and parasites in invading the host organism. The idea that alpha2-macroglobulin represents part of an ancient immune system is further supported by the homology of complement components C3, C4 and C5 with it (Armstrong et al., 1998; Little et al., 2004). alpha2-Macroglobulin (like some of the complement proteins) contains thiol ester groups that are not necessary for the interaction with peptidases, but can stabilise the binding of these and other molecules (Salvesen et al., 1981). |
| Pharmaceutical and biotech relevance | Having the property of specific binding of active endopeptidase molecules, alpha2-macroglobulin has found several applications in biotechnology. These include the isolation of active endopeptidases from crude biological preparations (Slot et al., 1988; Menendez-Arias et al., 1992; Nagase et al., 1994) and the active-site titration of peptidases (Osada et al., 1992). |
| Reviews | The review of Roberts (1985) is recommended. |
| Statistics for family I39 | Sequences: | 5759 |
| Identifiers: | 11 |
| Identifiers with PDB entries: | 6 |
| Downloadable files |
Sequence library (FastA format) |
| Sequence alignment (FastA format) |
| Phylogenetic tree (Newick format) |
