A2M
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4ACQ, 2P9R, 1BV8
Identifiers
Aliases	A2M, A2MD, CPAMD5, FWP007, S863-7, transcuprein, alpha-2-macroglobulin
External IDs	OMIM: 103950; MGI: 2449119; HomoloGene: 37248; GeneCards: A2M; OMA:A2M - orthologs
Gene location (Human) Chr. Chromosome 12 (human)[1] Band 12p13.31 Start 9,067,664 bp[1] End 9,116,229 bp[1]
Gene location (Mouse) Chr. Chromosome 6 (mouse)[2] Band 6 F1|6 57.49 cM Start 121,612,335 bp[2] End 121,656,186 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in lower lobe of lung upper lobe of lung upper lobe of left lung right lung Descending thoracic aorta visceral pleura pericardium tendon of biceps brachii epithelium of colon right coronary artery Top expressed in gastrula decidua corneal stroma Epithelium of choroid plexus choroid plexus of fourth ventricle ciliary body iris retinal pigment epithelium vestibular membrane of cochlear duct left lung lobe More reference expression data BioGPS n/a
Gene ontology Molecular function peptidase inhibitor activity interleukin-8 binding growth factor binding calcium-dependent protein binding protease binding protein binding serine-type endopeptidase inhibitor activity enzyme binding tumor necrosis factor binding endopeptidase inhibitor activity interleukin-1 binding signaling receptor binding GTPase activator activity Cellular component cytosol blood microparticle extracellular region extracellular exosome platelet alpha granule lumen extracellular space collagen-containing extracellular matrix Biological process blood coagulation, intrinsic pathway negative regulation of peptidase activity platelet degranulation extracellular matrix disassembly stem cell differentiation negative regulation of complement activation, lectin pathway regulation of small GTPase mediated signal transduction positive regulation of GTPase activity negative regulation of endopeptidase activity Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 2 232345 Ensembl ENSG00000175899 ENSMUSG00000030111 UniProt P01023 Q6GQT1 RefSeq (mRNA) NM_000014 NM_001347423 NM_001347424 NM_001347425 NM_175628 RefSeq (protein) NP_000005 NP_001334352 NP_001334353 NP_001334354 NP_783327 Location (UCSC) Chr 12: 9.07 – 9.12 Mb Chr 6: 121.61 – 121.66 Mb PubMed search [3] [4]
Wikidata
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α₂-Macroglobulin (α₂M) or alpha-2-macroglobulin 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.

α₂-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. α₂-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 α₂-macroglobulin. The concentration of α₂-macroglobulin rises 10-fold or more in the nephrotic syndrome when other lower molecular weight proteins are lost in the urine. The loss of α₂-macroglobulin into urine is prevented by its large size. The net result is that α₂-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 α₂-macroglobulin is composed of four identical subunits bound together by -S-S- bonds.^[5][6] In addition to tetrameric forms of α₂-macroglobulin, dimeric, and more recently monomeric αM protease inhibitors have been identified.^[7][8]

Each monomer of human α₂-macroglobulin is composed of several functional domains, including macroglobulin domains, a thiol ester-containing domain and a receptor-binding domain.^[9] Overall, α₂-macroglobulin is the largest major nonimmunoglobulin protein in human plasma.

The amino acid sequence of α₂-macroglobulin has been shown to be 71% the same as that of the pregnancy zone protein (PZP; also known as pregnancy-associated α₂-glycoprotein).^[10]

The α-macroglobulin (αM) family of proteins includes protease inhibitors,^[11] typified by the human tetrameric α₂-macroglobulin (α₂M); they belong to the MEROPS proteinase inhibitor family I39, clan IL. These protease inhibitors share several defining properties, which include (1) the ability to inhibit proteases from all catalytic classes, (2) the presence of a 'bait region' (also known as 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, (3) a similar protease inhibitory mechanism and (4) the inactivation of the inhibitory capacity by reaction of the thiol ester with small primary amines. αM protease inhibitors inhibit by steric hindrance.^[12] The mechanism involves protease cleavage of the bait region, a segment of the αM that is particularly susceptible to proteolytic cleavage, which initiates a conformational change such that the αM collapses about the protease. In the resulting αM-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 (1) the h-cysteinyl-g-glutamyl thiol ester becomes highly reactive and (2) a major conformational change exposes a conserved COOH-terminal receptor binding domain ^[13] (RBD). RBD exposure allows the αM protease complex to bind to clearance receptors and be removed from circulation.^[14] Tetrameric, dimeric, and, more recently, monomeric αM protease inhibitors have been identified.^[7][8]

α₂-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] α₂-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.

α₂-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 to 15% of copper in human plasma is chelated by α₂-macroglobulin.^[17]

α₂-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, α₂-macroglobulin is retained in the bloodstream. Increased production of all proteins means α₂-macroglobulin concentration increases. This increase has little adverse effect on the health but is used as a diagnostic clue.

An increase in α₂-Macroglobulin with normal amount of albumin mainly indicates acute and/or chronic inflammation.^[19]

A common variant (29.5%) (polymorphism) of α₂-macroglobulin leads to increased risk of Alzheimer's disease.^[20][21]

α₂-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.

• 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^{[permanent dead link‍]}
• alpha+2-Macroglobulin at the U.S. 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.