Family I39


Summary Holotypes Alignment Tree Genomes Structure Literature H-seq M-seq Architecture

Summary for family I39

NameInhibitor family I39 (alpha2M family)
Family type peptidaseI39.001 - alpha-2-macroglobulin (Homo sapiens), MEROPS Accession MER0018468 (inhibitor unit: 24-1474)
Content of familyInhibitor 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 inhibitedAlpha2-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 inhibitionCleavage 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 structurealpha2-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).
Distribution of family Bacteria details  
Archaea details  
Protozoa details  
Fungi -  
Plants details  
Animals details  
Viruses -  
Biological functionsIn 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 relevanceHaving 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).
ReviewsThe review of Roberts (1985) is recommended.
Statistics for family I39Sequences:5758
Identifiers with PDB entries:6
Downloadable files Sequence library (FastA format)
Sequence alignment (FastA format)
Phylogenetic tree (Newick format)
Other databases CATH
PFAM PF00207
SCOP 49411
Inhibitors and Homologues MEROPS ID Structure
pregnancy-zone proteinI39.003-
murinoglobulin 1I39.004-
murinoglobulin 2I39.005-
antigen CD109I39.006-
alpha-2-macroglobulin-like 1 proteinI39.007-
ECAM protein (Escherichia coli)I39.008Yes
complement component C3I39.950Yes
complement component C4I39.951Yes
complement component C5I39.952Yes
Family I39 non-peptidase homologuesnon-peptidase homologue-
Family I39 unassigned peptidasesunassignedYes