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91  structures 1381  species 11  interactions 2811  sequences 170  architectures

Family: A2M_N (PF01835)

Summary: MG2 domain

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This is the Wikipedia entry entitled "Alpha-2-Macroglobulin". More...

Alpha-2-Macroglobulin Edit Wikipedia article

Available structures
PDB Ortholog search: PDBe RCSB
Aliases A2M, A2MD, CPAMD5, FWP007, S863-7, transcuprein, alpha-2-macroglobulin
External IDs MGI: 2449119 HomoloGene: 37248 GeneCards: A2M
Gene location (Human)
Chromosome 12 (human)
Chr. Chromosome 12 (human)[1]
Chromosome 12 (human)
Genomic location for A2M
Genomic location for A2M
Band 12p13.31 Start 9,067,664 bp[1]
End 9,116,229 bp[1]
Species Human Mouse
RefSeq (mRNA)



RefSeq (protein)



Location (UCSC) Chr 12: 9.07 – 9.12 Mb Chr 6: 121.64 – 121.68 Mb
PubMed search [3] [4]
View/Edit Human View/Edit Mouse

alpha-2-Macroglobulin (α2M) is a large (720 KDa) plasma protein found in the blood. It is mainly produced by the liver, and also locally synthesized by macrophages, fibroblasts, and adrenocortical cells. In humans it is encoded by the A2M gene.

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.[5][6] In addition to tetrameric forms of alpha-2-macroglobulin, dimeric, and more recently monomeric aM protease inhibitors have been identified.[7][8]

Each monomer of human alpha-2-macroglobulin is composed of several functional domains, including macroglobulin domains, a thiol ester-containing domain and a receptor-binding domain.[9] Overall, alpha-2-Macroglobulin is the largest major nonimmunoglobulin protein in human plasma.


The alpha-macroglobulin (aM) family of proteins includes protease inhibitors,[10] 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' (aka. a sequence of amino acids in an α2-macroglobulin molecule, or a homologous protein, that contains scissile peptide bonds for those proteinases that it inhibits) 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.[11] 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 [12] (RBD). RBD exposure allows the aM protease complex to bind to clearance receptors and be removed from circulation.[13] Tetrameric, dimeric, and, more recently, monomeric aM protease inhibitors have been identified.[7][8]

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.[14] 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.

Fibrinolysis (simplified). Blue arrows denote stimulation, and red arrows inhibition.

alpha-2-Macroglobulin is known to bind zinc, as well as copper in plasma, even more strongly than albumin, and such it is also known as transcuprein.[15] 10-15% of copper in human plasma is chelated by alpha-2-macroglobulin.[16]


alpha-2-Macroglobulin levels are increased when the serum albumin levels are low,[17] which is most commonly seen 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).

A common variant (29.5%) (polymorphism) of alpha-2-macroglobulin leads to increased risk of Alzheimer's disease.[18][19]

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.


  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000175899 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000030111 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:". 
  4. ^ "Mouse PubMed Reference:". 
  5. ^ 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. 
  6. ^ 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. 
  7. ^ a b 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. 
  8. ^ a b 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. 
  9. ^ 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 2267405Freely accessible. PMID 17608619. 
  10. ^ Sottrup-Jensen L (July 1989). "Alpha-macroglobulins: structure, shape, and mechanism of proteinase complex formation". J. Biol. Chem. 264 (20): 11539–42. PMID 2473064. 
  11. ^ 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. 
  12. ^ 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. 
  13. ^ 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. 
  14. ^ 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 281280Freely accessible. PMID 7693593. 
  15. ^ Liu, Nanmei; Lo, Louis Shi-li; Askary, S. Hassan; Jones, LaTrice; Kidane, Theodros Z.; Nguyen, Trisha Trang Minh; Goforth, Jeremy; Chu, Yu-Hsiang; Vivas, Esther; Tsai, Monta; Westbrook, Terence; Linder, Maria C. (September 2007). "Transcuprein is a macroglobulin regulated by copper and iron availability". The Journal of Nutritional Biochemistry. 18 (9): 597–608. doi:10.1016/j.jnutbio.2006.11.005. PMC 4286573Freely accessible. 
  16. ^ Liu, Nan-mei; Nguyen, Trang; Kidane, Theodros; Moriya, Mizue; Goforth, Jeremy; Chu, Andy; Linder, Maria (6 March 2006). "Transcupreins are serum copper-transporters of the macroglobulin family, and may be regulated by iron and copper". The FASEB Journal. 20 (4): A553–A554. ISSN 0892-6638. 
  17. ^ Stevenson, FT; Greene, S; Kaysen, GA (January 1998). "Serum alpha 2-macroglobulin and alpha 1-inhibitor 3 concentrations are increased in hypoalbuminemia by post-transcriptional mechanisms". Kidney International. 53 (1): 67–75. doi:10.1046/j.1523-1755.1998.00734.x. PMID 9453001. 
  18. ^ 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. 
  19. ^ 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.

External links

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This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

MG2 domain Provide feedback

This is the MG2 (macroglobulin) domain of alpha-2-macroglobulin [1].

Literature references

  1. Janssen BJ, Huizinga EG, Raaijmakers HC, Roos A, Daha MR, Nilsson-Ekdahl K, Nilsson B, Gros P;, Nature. 2005;437:505-511.: Structures of complement component C3 provide insights into the function and evolution of immunity. PUBMED:16177781 EPMC:16177781

Internal database links

External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR002890

The proteinase-binding alpha-macroglobulins (A2M) [PUBMED:2473064] are large glycoproteins found in the plasma of vertebrates, in the hemolymph of some invertebrates and in reptilian and avian egg white. A2M-like proteins are able to inhibit all four classes of proteinases by a 'trapping' mechanism. They have 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, thus trapping the proteinase. The entrapped enzyme remains active against low molecular weight substrates, whilst its activity toward larger substrates is greatly reduced, due to steric hindrance. Following cleavage in the bait region, a thiol ester bond, formed between the side chains of a cysteine and a glutamine, is cleaved and mediates the covalent binding of the A2M-like protein to the proteinase.

This entry represents the MG2 (macroglobulin) domain of alpha-2-macroglobulin [PUBMED:16177781] and also includes homologous domains found in other proteins.

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Domain organisation

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Seed source: Pubmed:16177781
Previous IDs: none
Type: Domain
Author: Bateman A
Number in seed: 95
Number in full: 2811
Average length of the domain: 96.50 aa
Average identity of full alignment: 23 %
Average coverage of the sequence by the domain: 6.14 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 26740544 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 32.8 32.8
Trusted cut-off 32.8 32.8
Noise cut-off 32.7 32.7
Model length: 96
Family (HMM) version: 18
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Archea Archea Eukaryota Eukaryota
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There are 11 interactions for this family. More...

A2M_recep A2M_comp A2M_comp A2M A2M_N A2M_N_2 Thiol-ester_cl Stap_Strp_tox_C Trypsin Sushi A2M


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_N domain has been found. There are 91 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 sequence.

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