Alpha-2-macroglobulin (A2M)
The protein contains 1474 amino acids for an estimated molecular weight of 163291 Da.
Is able to inhibit all four classes of proteinases by a unique 'trapping' mechanism. This protein has a peptide stretch, called the 'bait region' which contains specific cleavage sites for different proteinases. When a proteinase cleaves the bait region, a conformational change is induced in the protein which traps the proteinase. The entrapped enzyme remains active against low molecular weight substrates (activity against high molecular weight substrates is greatly reduced). Following cleavage in the bait region, a thioester bond is hydrolyzed and mediates the covalent binding of the protein to the proteinase. (updated: Oct. 25, 2017)
Protein identification was indicated in the following studies:
- Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
- Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
- Wilson and co-workers. (2016) Comparison of the Proteome of Adult and Cord Erythroid Cells, and Changes in the Proteome Following Reticulocyte Maturation. Mol Cell Proteomics. 15(6), 1938-1946.
- Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
- D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
Methods
The following articles were analysed to gather the proteome content of erythrocytes.
The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.
| Publication | Identification 1 | Uniprot mapping 2 | Not mapped / Obsolete | TrEMBL | Swiss-Prot |
|---|---|---|---|---|---|
| Goodman (2013) | 2289 (gene list) | 2278 | 53 | 20599 | 2269 |
| Lange (2014) | 1234 | 1234 | 7 | 28 | 1224 |
| Hegedus (2015) | 2638 | 2622 | 0 | 235 | 2387 |
| Wilson (2016) | 1658 | 1528 | 170 | 291 | 1068 |
| d'Alessandro (2017) | 1826 | 1817 | 2 | 0 | 1815 |
| Bryk (2017) | 2090 | 2060 | 10 | 108 | 1942 |
| Chu (2018) | 1853 | 1804 | 55 | 362 | 1387 |
1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry
The compilation of older studies can be retrieved from the Red Blood Cell Collection database.
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
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| Variant | Description |
|---|---|
| dbSNP:rs226405 | |
| dbSNP:rs1800434 | |
| dbSNP:rs3180392 | |
| Probably interferes with the activity | |
| dbSNP:rs669 |
Biological Process
Blood coagulation
Blood coagulation, intrinsic pathway
Extracellular matrix disassembly
Extracellular matrix organization
Negative regulation of blood coagulation, intrinsic pathway
Negative regulation of complement activation, lectin pathway
Negative regulation of endopeptidase activity
Platelet activation
Platelet degranulation
Regulation of small GTPase mediated signal transduction
Small GTPase mediated signal transduction
Stem cell differentiation
Cellular Component
Blood microparticle
Collagen-containing extracellular matrix
Cytosol
Extracellular exosome
Extracellular region
Extracellular space
Platelet alpha granule lumen
Molecular Function
Calcium-dependent protein binding
Endopeptidase inhibitor activity
Enzyme binding
Growth factor binding
GTPase activator activity
Interleukin-1 binding
Interleukin-8 binding
Protease binding
Serine-type endopeptidase inhibitor activity
Signaling receptor binding
Tumor necrosis factor binding
The reference OMIM entry for this protein is 103950
Alpha-2-macroglobulin; a2m
Macroglobulin, alpha-2
DESCRIPTION
A2M is a 718-kD homotetrameric glycoprotein of plasma and extracellular spaces that was first recognized as a broad spectrum protease inhibitor. A2M is activated by proteases with which it interacts, and this proteolytic activation causes a conformational change that traps the protease within the A2M homotetramer. In addition, A2M contains several independent domains that function as carriers of specific growth factors and/or binding sites for receptors. Activation of A2M by proteases alters the interaction of A2M with these ligands and induces cell signaling (summary by Mantuano et al., 2008).CLONING
Using synthetic oligonucleotides as hybridization probes, Kan et al. (1985) isolated A2M cDNA clones from a human liver cDNA library. The coding sequence predicted a 1,451-amino acid polypeptide. Human A2M is a tetramer of 4 identical 185-kD subunits arranged as a pair of dimers, each consisting of 2 disulfide-linked monomers. The protein has a bait region composed of peptide bonds for plasma proteases and a thiol ester bond which, when hydrolyzed, leads to covalent bonding between the protease and A2M.GENE STRUCTURE
Matthijs et al. (1992) demonstrated that the A2M gene spans approximately 48 kb and consists of 36 exons, from 21 to 229 bp in size and with consensus splice sites. Intron sizes range from 125 bp to 7.5 kb. The A2M gene is present in single copy in the haploid genome. Umans et al. (1994) found that the homologous gene in the mouse contains 36 exons, coding for a 4.8-kb cDNA. Including putative control elements in the 5-prime flanking region, the gene covers about 45 kb. The promoter region of the mouse A2m gene differed considerably from the known promoter sequences of the human and rat genes.MAPPING
Kan et al. (1985) assigned the A2M locus to chromosome 12 by Southern blot analysis of DNA from a panel of mouse/human somatic cell hybrids, using A2M cDNA as a hybridization probe. Fukushima et al. (1988) assigned the A2M locus to 12p13.3-p12.3 by in situ hybridization. Assignment of the A2M gene to human chromosome 12p13-p12.2 was confirmed by Marynen et al. (1989) by use of in situ hybridization and somatic cell hybrid DNA analysis. Devriendt et al. (1989) also assigned A2M to 12p13-p12 by analysis of somatic cell hybrids and in situ hybridization. They showed, furthermore, that a closely related gene for pregnancy-zone protein (PZP; 176420) and an A2M pseudogene map to the same region. Hilliker et al. (1992) showed that the gene is located on mouse chromosome 6 band F1-G3 in a syntenic group that has its human counterpart on 12p13-p12.GENE FUNCTION
Alpha-2-macroglobulin is, like alpha-1-antitrypsin, alpha-2-antiplasmin, and antithrombin III, a protease inhibitor. It inhibits many proteases, including trypsin, thrombin, and collagenase (Bergqvist and Nilsson, 1979). Mantuano et al. (2008) used isolated recombinant human A2M protein fragments, which they called FP3 and FP6, to characterize the cellular functions of specific A2M domains. FP3 contains residues 591 to 774 of A2M and includes the growth factor carrier sites, and FP6 contains residues 1242 to 1451 of A2M and includes the LRP1 (107770) recognition domain. FP6 rapidly and robustly activated Akt (see 164730) and Erk/MAP kinases (see 176948) in cultured rat Schwann cells and PC12 rat pheochromocytoma cells. FP6 also promoted neurite outgrowth and expression of Gap43 (162060). These cell signaling even ... More on the omim web site
May 12, 2019: Protein entry updated
Automatic update: model status changed
Nov. 16, 2018: Protein entry updated
Automatic update: model status changed
Feb. 5, 2018: Protein entry updated
Automatic update: Entry updated from uniprot information.
Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated
Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated
Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated
June 20, 2017: Protein entry updated
Automatic update: comparative model was added.
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 103950 was added.
Jan. 27, 2016: Protein entry updated
Automatic update: model status changed
Jan. 24, 2016: Protein entry updated
Automatic update: model status changed