Summary: Alpha-2-macroglobulin family
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Alpha-2-Macroglobulin Edit Wikipedia article
Crystal structure of alpha-2-macroglobulin. Rendered from PDB 2P9R.
|Locus||Chr. 12 p13.31|
|A-macroglobulin complement component|
n-terminally truncated c3dg fragment
|MG2 (macroglobulin) domain|
|Alpha-2-macroglobulin family N-terminal region|
|A2M receptor domain region|
receptor domain from alpha-2-macroglobulin
alpha-2-Macroglobulin, also known as α2-macroglobulin and abbreviated as α2M and A2M, is a large plasma protein found in the blood. It is produced by the liver, and is a major component of the alpha-2 band in protein electrophoresis.
Alpha-2-Macroglobulin is the largest major nonimmunoglobulin protein in plasma. The alpha-2-macroglobulin molecule is synthesized mainly in liver, but also locally by macrophages, fibroblasts, and adrenocortical cells.
Alpha 2 macroglobulin acts as an antiprotease and is able to inactivate an enormous variety of proteinases. It functions as an inhibitor of fibrinolysis by inhibiting plasmin and kallikrein. It functions as an inhibitor of coagulation by inhibiting thrombin. Alpha-2-macroglobulin may act as a carrier protein because it also binds to numerous growth factors and cytokines, such as platelet-derived growth factor, basic fibroblast growth factor, TGF-β, insulin, and IL-1β.
No specific deficiency with associated disease has been recognized, and no disease state is attributed to low concentrations of alpha-2-macroglobulin.
The concentration of alpha-2-macroglobulin rises 10-fold or more in the nephrotic syndrome when other lower molecular weight proteins are lost in the urine. The loss of alpha-2-macroglobulin into urine is prevented by its large size. The net result is that alpha-2-macroglobulin reaches serum levels equal to or greater than those of albumin in the nephrotic syndrome, which has the effect of maintaining oncotic pressure.
Human alpha-2-macroglobulin is composed of four identical subunits bound together by -S-S- bonds. In addition to tetrameric forms of alpha-2-macroglobulin, dimeric, and more recently monomeric aM protease inhibitors have been identified.
Each monomer of Human alpha-2-macroglobulin is composed of many functional domains, including macroglobulin domains, a thiol ester-containing domain and a receptor-binding domain.
The alpha-macroglobulin (aM) family of proteins includes protease inhibitors, typified by the human tetrameric alpha-2-macroglobulin (a2M); they belong to the MEROPS proteinase inhibitor family I39, clan IL. These protease inhibitors share several defining properties, which include (i) the ability to inhibit proteases from all catalytic classes, (ii) the presence of a 'bait region' and a thiol ester, (iii) a similar protease inhibitory mechanism and (iv) the inactivation of the inhibitory capacity by reaction of the thiol ester with small primary amines. aM protease inhibitors inhibit by steric hindrance. The mechanism involves protease cleavage of the bait region, a segment of the aM that is particularly susceptible to proteolytic cleavage, which initiates a conformational change such that the aM collapses about the protease. In the resulting aM-protease complex, the active site of the protease is sterically shielded, thus substantially decreasing access to protein substrates. Two additional events occur as a consequence of bait region cleavage, namely (i) the h-cysteinyl-g-glutamyl thiol ester becomes highly reactive and (ii) a major conformational change exposes a conserved COOH-terminal receptor binding domain  (RBD). RBD exposure allows the aM protease complex to bind to clearance receptors and be removed from circulation. Tetrameric, dimeric, and, more recently, monomeric aM protease inhibitors have been identified.
Alpha-2-macroglobulin is able to inactivate an enormous variety of proteinases (including serine-, cysteine-, aspartic- and metalloproteinases). It functions as an inhibitor of fibrinolysis by inhibiting plasmin and kallikrein. It functions as an inhibitor of coagulation by inhibiting thrombin.
Alpha-2-macroglobulin has in its structure a 35 amino acid "bait" region. Proteinases binding and cleaving the bait region become bound to α2M. The proteinase-α2M complex is recognised by macrophage receptors and cleared from the system.
Alpha-2-macroglobulin levels are increased in nephrotic syndrome, a condition wherein the kidneys start to leak out some of the smaller blood proteins. Because of its size, alpha-2-macroglobulin is retained in the bloodstream. Increased production of all proteins means alpha-2-macroglobulin concentration increases. This increase has little adverse effect on the health, but is used as a diagnostic clue. Longstanding chronic renal failure can lead to amyloid by alpha-2-macroglobulin (see main article: amyloid).
Alpha-2-macroglobulin binds to and removes the active forms of the gelatinase (MMP-2 and MMP-9) from the circulation via scavenger receptors on the phagocytes.
- Andersen GR, Koch TJ, Dolmer K, Sottrup-Jensen L, Nyborg J (October 1995). "Low resolution X-ray structure of human methylamine-treated alpha 2-macroglobulin". J. Biol. Chem. 270 (42): 25133–41. doi:10.1074/jbc.270.42.25133. PMID 7559647.
- Sottrup-Jensen L, Stepanik TM, Kristensen T, Wierzbicki DM, Jones CM, Lønblad PB et al. (1984). "Primary structure of human alpha 2-macroglobulin. V. The complete structure.". J Biol Chem 259 (13): 8318–27. PMID 6203908.
- Dodds AW, Law SK (December 1998). "The phylogeny and evolution of the thioester bond-containing proteins C3, C4 and alpha 2-macroglobulin". Immunol. Rev. 166: 15–26. doi:10.1111/j.1600-065X.1998.tb01249.x. PMID 9914899.
- Armstrong PB, Quigley JP (1999). "Alpha2-macroglobulin: an evolutionarily conserved arm of the innate immune system". Dev. Comp. Immunol. 23 (4-5): 375–90. doi:10.1016/s0145-305x(99)00018-x. PMID 10426429.
- Doan N, Gettins PG (2007). "Human alpha2-macroglobulin is composed of multiple domains, as predicted by homology with complement component C3.". Biochem J 407 (1): 23–30. doi:10.1042/BJ20070764. PMC 2267405. PMID 17608619.
- Sottrup-Jensen L (July 1989). "Alpha-macroglobulins: structure, shape, and mechanism of proteinase complex formation". J. Biol. Chem. 264 (20): 11539–42. PMID 2473064.
- Enghild JJ, Salvesen G, Thøgersen IB, Pizzo SV (July 1989). "Proteinase binding and inhibition by the monomeric alpha-macroglobulin rat alpha 1-inhibitor-3". J. Biol. Chem. 264 (19): 11428–35. PMID 2472396.
- Enghild JJ, Thøgersen IB, Roche PA, Pizzo SV (February 1989). "A conserved region in alpha-macroglobulins participates in binding to the mammalian alpha-macroglobulin receptor". Biochemistry 28 (3): 1406–12. doi:10.1021/bi00429a069. PMID 2469470.
- Van Leuven F, Cassiman JJ, Van den Berghe H (December 1986). "Human pregnancy zone protein and alpha 2-macroglobulin. High-affinity binding of complexes to the same receptor on fibroblasts and characterization by monoclonal antibodies". J. Biol. Chem. 261 (35): 16622–5. PMID 2430968.
- de Boer JP, Creasey AA, Chang A, Abbink JJ, Roem D, Eerenberg AJ, Hack CE, Taylor FB (December 1993). "Alpha-2-macroglobulin functions as an inhibitor of fibrinolytic, clotting, and neutrophilic proteinases in sepsis: studies using a baboon model". Infect. Immun. 61 (12): 5035–43. PMC 281280. PMID 7693593.
- Blacker D, Wilcox MA, Laird NM, Rodes L, Horvath SM, Go RC, Perry R, Watson B, Bassett SS, McInnis MG, Albert MS, Hyman BT, Tanzi RE (August 1998). "Alpha-2 macroglobulin is genetically associated with Alzheimer disease". Nat. Genet. 19 (4): 357–60. doi:10.1038/1243. PMID 9697696.
- Kovacs DM (July 2000). "alpha2-macroglobulin in late-onset Alzheimer's disease". Exp. Gerontol. 35 (4): 473–9. doi:10.1016/S0531-5565(00)00113-3. PMID 10959035.
- McPherson & Pincus: Henry's Clinical Diagnosis and Management by Laboratory Methods, 21st ed.
- Firestein: Kelley's Textbook of Rheumatology, 8th edition.
- The MEROPS online database for peptidases and their inhibitors: I39.001
- alpha 2-Macroglobulin at the US National Library of Medicine Medical Subject Headings (MeSH)
- A2M human gene location in the UCSC Genome Browser.
- A2M human gene details in the UCSC Genome Browser.
Alpha-2-macroglobulin family Provide feedback
This family includes the C-terminal region of the alpha-2-macroglobulin family.
Zanotti G, Bassetto A, Battistutta R, Folli C, Arcidiaco P, Stoppini M, Berni R; , Biochim Biophys Acta 2000;1478:232-238.: Structure at 1.44 A resolution of an N-terminally truncated form of the rat serum complement C3d fragment. PUBMED:10825534 EPMC:10825534
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR001599
This entry contains serum complement C3 and C4 precursors and alpha-macrogrobulins.
The alpha-macroglobulin (aM) family of proteins includes protease inhibitors [PUBMED:2473064], typified by the human tetrameric a2-macroglobulin (a2M); they belong to the MEROPS proteinase inhibitor family I39, clan IL. These protease inhibitors share several defining properties, which include (i) the ability to inhibit proteases from all catalytic classes, (ii) the presence of a 'bait region' and a thiol ester, (iii) a similar protease inhibitory mechanism and (iv) the inactivation of the inhibitory capacity by reaction of the thiol ester with small primary amines. aM protease inhibitors inhibit by steric hindrance [PUBMED:2472396]. The mechanism involves protease cleavage of the bait region, a segment of the aM that is particularly susceptible to proteolytic cleavage, which initiates a conformational change such that the aM collapses about the protease. In the resulting aM-protease complex, the active site of the protease is sterically shielded, thus substantially decreasing access to protein substrates. Two additional events occur as a consequence of bait region cleavage, namely (i) the h-cysteinyl-g-glutamyl thiol ester becomes highly reactive and (ii) a major conformational change exposes a conserved COOH-terminal receptor binding domain [PUBMED:2469470] (RBD). RBD exposure allows the aM protease complex to bind to clearance receptors and be removed from circulation [PUBMED:2430968]. Tetrameric, dimeric, and, more recently, monomeric aM protease inhibitors have been identified [PUBMED:9914899, PUBMED:10426429].
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Molecular function||endopeptidase inhibitor activity (GO:0004866)|
- the number of sequences which exhibit this architecture
a textual description of the architecture, e.g. Gla, EGF x 2, Trypsin.
This example describes an architecture with one
Gladomain, followed by two consecutive
EGFdomains, and finally a single
- the UniProt description of the protein sequence
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Members of the immunoglobulin superfamily are found in hundreds of proteins of different functions. Examples include antibodies, the giant muscle kinase titin and receptor tyrosine kinases. Immunoglobulin-like domains may be involved in protein-protein and protein-ligand interactions. The superfamily can be divided into discrete structural sets, by the presence or absence of beta-strands in the structure and the length of the domains . Proteins containing domains of the C1 and V-sets are mostly molecules of the vertebrate immune system. Proteins of the C2-set are mainly lymphocyte antigens, this differs from the composition of the C2-set as originally proposed . The I-set is intermediate in structure between the C1 and V-sets and is found widely in cell surface proteins as well as intracellular muscle proteins.
The clan contains the following 24 members:A2M Adeno_E3_CR1 Adhes-Ig_like C1-set C2-set C2-set_2 Herpes_gE Herpes_gI Herpes_glycop_D I-set ICAM_N ig Ig_2 Ig_3 Ig_Tie2_1 IZUMO K1 Lep_receptor_Ig Marek_A PTCRA Receptor_2B4 SVA V-set V-set_CD47
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Curation and family details
|Author:||Finn RD, Sammut SJ|
|Number in seed:||131|
|Number in full:||2819|
|Average length of the domain:||88.80 aa|
|Average identity of full alignment:||26 %|
|Average coverage of the sequence by the domain:||5.98 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||17|
|Download:||download the raw HMM for this family|
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There are 5 interactions for this family. More...
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For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the A2M domain has been found. There are 58 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.
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