Please note: this site relies heavily on the use of javascript. Without a javascript-enabled browser, this site will not function correctly. Please enable javascript and reload the page, or switch to a different browser.
107  structures 2519  species 0  interactions 6638  sequences 434  architectures

Family: MG2 (PF01835)

Summary: MG2 domain

Pfam includes annotations and additional family information from a range of different sources. These sources can be accessed via the tabs below.

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

Alpha-2-Macroglobulin Edit Wikipedia article

Available structures
PDBOrtholog search: PDBe RCSB
AliasesA2M, A2MD, CPAMD5, FWP007, S863-7, transcuprein, alpha-2-macroglobulin
External IDsOMIM: 103950 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
Band12p13.31Start9,067,664 bp[1]
End9,116,229 bp[1]
RefSeq (mRNA)



RefSeq (protein)



Location (UCSC)Chr 12: 9.07 – 9.12 MbChr 6: 121.64 – 121.68 Mb
PubMed search[3][4]
View/Edit HumanView/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 amino acid sequence of alpha-2-macroglobulin has been shown to be 71% the same as that of the Pregnancy zone protein.[10]


The alpha-macroglobulin (aM) family of proteins includes protease inhibitors,[11] 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.[12] 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 [13] (RBD). RBD exposure allows the aM protease complex to bind to clearance receptors and be removed from circulation.[14] 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.[15] 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.[16] 10-15% of copper in human plasma is chelated by alpha-2-macroglobulin.[17]


alpha-2-Macroglobulin levels are increased when the serum albumin levels are low,[18] 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.[19][20]

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:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  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 2267405. PMID 17608619.
  10. ^ Devriendt K, Van den Berghe H, Cassiman JJ, Marynen P (1991). “Primary structure of pregnancy zone protein. Molecular cloning of a full-length PZP cDNA clone by the polymerase chain reaction”. Biochimica et Biophysica Acta. 1088(1): 95-103
  11. ^ Sottrup-Jensen L (July 1989). "Alpha-macroglobulins: structure, shape, and mechanism of proteinase complex formation". J. Biol. Chem. 264 (20): 11539–42. PMID 2473064.
  12. ^ 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.
  13. ^ 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.
  14. ^ 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.
  15. ^ 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.
  16. ^ 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 4286573. PMID 17363239.
  17. ^ 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. doi:10.1096/fasebj.20.4.A553-d. ISSN 0892-6638.
  18. ^ 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.
  19. ^ 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.
  20. ^ 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

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

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 in eukaryotes [1]. Alpha-2-macroglobulins (A2Ms) are plasma proteins that trap and inhibit a broad range of proteases and are major components of the eukaryotic innate immune system. However, A2M-like proteins were identified in pathogenically invasive bacteria and species that colonize higher eukaryotes. This domain is found in eukaryotic and bacterial proteins. In human A2Ms, this domain is termed macroglobulin-like (MG) domain 2 and in Salmonella enterica ser A2Ms, this is domain 4 [2] [3].

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

  2. Wong SG, Dessen A;, Nat Commun. 2014;5:4917.: Structure of a bacterial alpha2-macroglobulin reveals mimicry of eukaryotic innate immunity. PUBMED:25221932 EPMC:25221932

  3. Marrero A, Duquerroy S, Trapani S, Goulas T, Guevara T, Andersen GR, Navaza J, Sottrup-Jensen L, Gomis-Ruth FX;, Angew Chem Int Ed Engl. 2012;51:3340-3344.: The crystal structure of human alpha2-macroglobulin reveals a unique molecular cage. PUBMED:22290936 EPMC:22290936

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 ]. A2M-like proteins have been identified in pathogenically invasive bacteria and species that colonize higher eukaryotes. This domain is found in eukaryotic and bacterial proteins. In human A2Ms, this domain is termed macroglobulin-like (MG) domain 2 and in Salmonella enterica ser A2Ms, this is domain 4 [ PUBMED:25221932 , PUBMED:22290936 ].

Gene Ontology

The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

Loading domain graphics...

Pfam Clan

This family is a member of clan E-set (CL0159), which has the following description:

This clan includes a diverse range of domains that have an Ig-like fold and appear to be distantly related to each other. The clan includes: PKD domains, cadherins and several families of bacterial Ig-like domains as well as viral tail fibre proteins. it also includes several Fibronectin type III domain-containing families.

The clan contains the following 238 members:

A2M A2M_BRD A2M_recep AA9 Adeno_GP19K AlcCBM31 Alpha-amylase_N Alpha_adaptinC2 Alpha_E2_glycop Anth_Ig Arch_flagellin aRib Arylsulfotran_N ASF1_hist_chap ATG19 BACON BACON_2 BatD BIg21 Big_1 Big_10 Big_11 Big_12 Big_13 Big_2 Big_3 Big_3_2 Big_3_3 Big_3_4 Big_3_5 Big_4 Big_5 Big_6 Big_7 Big_8 Big_9 Bile_Hydr_Trans BiPBP_C bMG1 bMG10 bMG3 bMG5 bMG6 BslA BsuPI Cadherin Cadherin-like Cadherin_2 Cadherin_3 Cadherin_4 Cadherin_5 Cadherin_pro CagX Calx-beta Candida_ALS_N CARDB CBM39 CBM_X2 CD45 CelD_N Ceramidse_alk_C CHB_HEX_C CHB_HEX_C_1 ChitinaseA_N ChiW_Ig_like Chlam_OMP6 CHU_C Coatamer_beta_C COP-gamma_platf CopC CshA_repeat Cyc-maltodext_N Cytomega_US3 DsbC DUF11 DUF1410 DUF1425 DUF1929 DUF2271 DUF3244 DUF3327 DUF3416 DUF3458 DUF3501 DUF3823_C DUF3859 DUF4165 DUF4179 DUF4426 DUF4469 DUF4625 DUF4879 DUF4959 DUF4981 DUF4982 DUF4998 DUF5001 DUF5008 DUF5011 DUF5065 DUF5115 DUF525 DUF5643 DUF6383 DUF916 EB_dh ECD EpoR_lig-bind ERAP1_C EstA_Ig_like Expansin_C Filamin FixG_C Flavi_glycop_C FlgD_ig fn3 Fn3-like fn3_2 fn3_4 fn3_5 fn3_6 FN3_7 Fn3_assoc fn3_PAP GBS_Bsp-like Glucodextran_B Glyco_hydro2_C5 Glyco_hydro_2 Gmad2 GMP_PDE_delta GPI-anchored Hanta_G1 He_PIG HECW_N HemeBinding_Shp Hemocyanin_C Herpes_BLLF1 HYR IFNGR1 Ig_GlcNase Ig_mannosidase IL12p40_C Il13Ra_Ig IL17R_fnIII_D1 IL17R_fnIII_D2 IL2RB_N1 IL3Ra_N IL4Ra_N IL6Ra-bind Inhibitor_I42 Inhibitor_I71 InlK_D3 Integrin_alpha2 Interfer-bind Invasin_D3 IRK_C IrmA Iron_transport LEA_2 Lep_receptor_Ig LIFR_N Lipase_bact_N LPMO_10 LRR_adjacent LTD Mannosidase_ig MetallophosC MG1 MG2 MG3 MG4 Mo-co_dimer N_BRCA1_IG Na_K-ATPase NEAT Neocarzinostat Neurexophilin NPCBM_assoc PapD_C PBP-Tp47_c Peptidase_C25_C Phlebo_G2_C PhoD_N PKD PKD_2 PKD_3 PKD_4 PKD_5 PKD_6 Por_Secre_tail Pox_vIL-18BP Psg1 PTP_tm Pur_ac_phosph_N Qn_am_d_aII Qn_am_d_aIII RabGGT_insert Reeler REJ RET_CLD1 RET_CLD3 RET_CLD4 RGI_lyase RHD_dimer Rho_GDI Rib RibLong SCAB-Ig SKICH SLAM SoxZ SprB SusE SVA SWM_repeat T2SS-T3SS_pil_N Tafi-CsgC TarS_C1 TcA_RBD TcfC TIG TIG_2 TIG_plexin TIG_SUH Tissue_fac Top6b_C Transglut_C Transglut_N TRAP_beta TraQ_transposon UL16 Velvet WIF Wzt_C Y_Y_Y YBD ZirS_C Zona_pellucida


We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets and the UniProtKB sequence database. More...

View options

We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.

Representative proteomes UniProt
Jalview View  View  View  View  View  View  View 
HTML View             
PP/heatmap 1            

1Cannot generate PP/Heatmap alignments for seeds; no PP data available

Key: ✓ available, x not generated, not available.

Format an alignment

Representative proteomes UniProt

Download options

We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.

Representative proteomes UniProt
Raw Stockholm Download   Download   Download   Download   Download   Download   Download  
Gzipped Download   Download   Download   Download   Download   Download   Download  

You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

HMM logo

HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...


This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

Note: You can also download the data file for the tree.

Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: Pubmed:16177781
Previous IDs: A2M_N;
Type: Domain
Sequence Ontology: SO:0000417
Author: Bateman A
Number in seed: 78
Number in full: 6638
Average length of the domain: 96.50 aa
Average identity of full alignment: 22 %
Average coverage of the sequence by the domain: 6.06 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 57096847 -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: 21
Download: download the raw HMM for this family

Species distribution

Sunburst controls


Weight segments by...

Change the size of the sunburst


Colour assignments

Archea Archea Eukaryota Eukaryota
Bacteria Bacteria Other sequences Other sequences
Viruses Viruses Unclassified Unclassified
Viroids Viroids Unclassified sequence Unclassified sequence


Align selected sequences to HMM

Generate a FASTA-format file

Clear selection

This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the adjacent tab. More...

Loading sunburst data...

Tree controls


The tree shows the occurrence of this domain across different species. More...


Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.


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 MG2 domain has been found. There are 107 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.

Loading structure mapping...