Editing Alpha-2-Macroglobulin

{{Short description|Large plasma protein found in the blood}}
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{{Lowercase}}
{{Infobox gene}}

'''α<sub>2</sub>-Macroglobulin''' ('''α<sub>2</sub>M''') 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.

α<sub>2</sub>-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]]. α<sub>2</sub>-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 α<sub>2</sub>-macroglobulin. The concentration of α<sub>2</sub>-macroglobulin rises 10-fold or more in the nephrotic syndrome when other lower molecular weight proteins are lost in the urine. The loss of α<sub>2</sub>-macroglobulin into urine is prevented by its large size. The net result is that α<sub>2</sub>-macroglobulin reaches serum levels equal to or greater than those of albumin in the nephrotic syndrome, which has the effect of maintaining [[oncotic pressure]].

== Structure ==
Human α<sub>2</sub>-macroglobulin is composed of four identical subunits bound together by [[SS-bond#Occurrence in proteins|-S-S- bonds]].<ref name="Andersen_1995">{{cite journal | vauthors = Andersen GR, Koch TJ, Dolmer K, Sottrup-Jensen L, Nyborg J | title = Low resolution X-ray structure of human methylamine-treated alpha 2-macroglobulin | journal = Journal of Biological Chemistry | volume = 270 | issue = 42 | pages = 25133–25141 | date = October 1995 | pmid = 7559647 | doi = 10.1074/jbc.270.42.25133 | s2cid = 86387917 | doi-access = free }}</ref><ref name="SottrupJensen_1984">{{cite journal | vauthors = Sottrup-Jensen L, Stepanik TM, Kristensen T, Wierzbicki DM, Jones CM, Lønblad PB | title = Primary structure of human alpha 2-macroglobulin. V. The complete structure. | journal = Journal of Biological Chemistry | volume = 259 | issue = 13 | pages = 8318–8327 | date = Jul 1984 | pmid = 6203908 | doi = 10.1016/S0021-9258(17)39730-2 | doi-access = free }}</ref> In addition to [[tetramer|tetrameric]] forms of α<sub>2</sub>-macroglobulin, [[dimer (chemistry)|dimeric]], and more recently [[monomer|monomeric]] αM protease inhibitors have been identified.<ref name="Dodds_1998">{{cite journal | vauthors = Dodds AW, Law SK | title = The phylogeny and evolution of the thioester bond-containing proteins C3, C4 and alpha 2-macroglobulin | journal = Immunological Reviews | volume = 166 | pages = 15–26 | date = December 1998 | pmid = 9914899 | doi = 10.1111/j.1600-065X.1998.tb01249.x | s2cid = 84262599 }}</ref><ref name="Armstrong_1999">{{cite journal | vauthors = Armstrong PB, Quigley JP | title = Alpha2-macroglobulin: an evolutionarily conserved arm of the innate immune system | journal = Developmental and Comparative Immunology | volume = 23 | issue = 4–5 | pages = 375–390 | year = 1999 | pmid = 10426429 | doi = 10.1016/s0145-305x(99)00018-x }}</ref>

Each monomer of human α<sub>2</sub>-macroglobulin is composed of several functional domains, including macroglobulin domains, a thiol ester-containing domain and a receptor-binding domain.<ref name="Doan_2007">{{cite journal | vauthors = Doan N, Gettins PG | title = Human alpha2-macroglobulin is composed of multiple domains, as predicted by homology with complement component C3. | journal = The Biochemical Journal | volume = 407 | issue = 1 | pages = 23–30 | date = Oct 2007 | pmid = 17608619 | pmc = 2267405 | doi = 10.1042/BJ20070764 }}</ref> Overall, α<sub>2</sub>-macroglobulin is the largest major nonimmunoglobulin protein in human plasma.

The [[amino acid sequence]] of α<sub>2</sub>-macroglobulin has been shown to be 71% the same as that of the [[pregnancy zone protein]] (PZP; also known as pregnancy-associated α<sub>2</sub>-glycoprotein).<ref>{{cite journal | vauthors = Devriendt K, Van den Berghe H, Cassiman JJ, Marynen P | title = Primary structure of pregnancy zone protein. Molecular cloning of a full-length PZP cDNA clone by the polymerase chain reaction | journal = Biochimica et Biophysica Acta | volume = 1088 | issue = 1 | pages = 95–103 | date = Jan 1991 | pmid = 1989698 | doi = 10.1016/0167-4781(91)90157-h }}</ref>

==Function==
The [[α-macroglobulin]] (αM) [[protein family|family of proteins]] includes [[protease inhibitor (biology)|protease inhibitor]]s,<ref name="SottrupJensen_1989">{{cite journal | vauthors = Sottrup-Jensen L | title = Alpha-macroglobulins: structure, shape, and mechanism of proteinase complex formation | journal = Journal of Biological Chemistry | volume = 264 | issue = 20 | pages = 11539–11542 | date = July 1989 | pmid = 2473064 | doi = 10.1016/S0021-9258(18)80094-1 | doi-access = free }}</ref> typified by the [[Homo sapiens|human]] [[tetrameric protein|tetrameric]] α<sub>2</sub>-macroglobulin (α<sub>2</sub>M); they belong to the MEROPS [[proteinase]] inhibitor family I39, clan IL. These protease inhibitors share several defining properties, which include (1) the ability to [[Enzyme inhibitor|inhibit]] [[protease]]s from all [[catalytic]] classes, (2) the presence of a 'bait region' (also known as a sequence of [[amino acids]] in an α<sub>2</sub>-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 [[amine]]s. αM [[Protease inhibitor (biology)|protease inhibitor]]s inhibit by [[steric]] hindrance.<ref name="Enghild_1989">{{cite journal | vauthors = Enghild JJ, Salvesen G, Thøgersen IB, Pizzo SV | title = Proteinase binding and inhibition by the monomeric alpha-macroglobulin rat alpha 1-inhibitor-3 | journal = Journal of Biological Chemistry | volume = 264 | issue = 19 | pages = 11428–11435 | date = July 1989 | pmid = 2472396 | doi = 10.1016/S0021-9258(18)60482-X | doi-access = free }}</ref> The [[Nuclear receptor#Mechanism of action|mechanism]] involves protease [[Bond cleavage|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 [[steric effects|sterically]] shielded, thus substantially decreasing access to [[protein]] [[substrate (biochemistry)|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 [[Protein structure|conformational]] change exposes a [[conserved sequence|conserved]] [[COOH-terminal]] [[receptor (biochemistry)|receptor]] [[Binding (molecular)|binding]] domain <ref name="Enghild_1989a">{{cite journal | vauthors = Enghild JJ, Thøgersen IB, Roche PA, Pizzo SV | title = A conserved region in alpha-macroglobulins participates in binding to the mammalian alpha-macroglobulin receptor | journal = Biochemistry | volume = 28 | issue = 3 | pages = 1406–1412 | date = February 1989 | pmid = 2469470 | doi = 10.1021/bi00429a069 }}</ref> (RBD). RBD exposure allows the αM protease [[Protein complex|complex]] to [[Molecular binding|bind]] to clearance [[Receptor (biochemistry)|receptors]] and be removed from circulation.<ref name="Van_Leuven_1986">{{cite journal | vauthors = Van Leuven F, Cassiman JJ, Van den Berghe H | title = Human pregnancy zone protein and alpha 2-macroglobulin. High-affinity binding of complexes to the same receptor on fibroblasts and characterization by monoclonal antibodies | journal = Journal of Biological Chemistry | volume = 261 | issue = 35 | pages = 16622–16625 | date = December 1986 | pmid = 2430968 | doi = 10.1016/S0021-9258(18)66612-8 | doi-access = free }}</ref> Tetrameric, dimeric, and, more recently, monomeric αM protease inhibitors have been identified.<ref name="Dodds_1998" /><ref name="Armstrong_1999" />

α<sub>2</sub>-Macroglobulin is able to inactivate an enormous variety of proteinases (including [[serine proteinase|serine]]-, [[cysteine-proteinase|cysteine]]-, [[aspartic proteinase|aspartic]]- and [[metalloproteinase]]s). It functions as an inhibitor of [[fibrinolysis]] by inhibiting [[plasmin]] and kallikrein. It functions as an inhibitor of [[coagulation]] by inhibiting [[thrombin]].<ref name="de_Boer_1993">{{cite journal | vauthors = de Boer JP, Creasey AA, Chang A, Abbink JJ, Roem D, Eerenberg AJ, Hack CE, Taylor FB | title = Alpha-2-macroglobulin functions as an inhibitor of fibrinolytic, clotting, and neutrophilic proteinases in sepsis: studies using a baboon model | journal = Infection and Immunity | volume = 61 | issue = 12 | pages = 5035–5043 | date = December 1993 | pmid = 7693593 | pmc = 281280 | doi = 10.1128/iai.61.12.5035-5043.1993 }}</ref> α<sub>2</sub>-Macroglobulin has in its structure a 35 amino acid "bait" region. Proteinases binding and cleaving the bait region become bound to α<sub>2</sub>M. The proteinase–α<sub>2</sub>M complex is recognised by macrophage receptors and cleared from the system.

[[Image:Fibrinolysis.svg|center|framed|Fibrinolysis (simplified). Blue arrows denote stimulation, and red arrows inhibition.]]

α<sub>2</sub>-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'''.<ref>{{cite journal | vauthors = Liu N, Lo LS, Askary SH, Jones L, Kidane TZ, Nguyen TT, Goforth J, Chu YH, Vivas E, Tsai M, Westbrook T, Linder MC | title = Transcuprein is a macroglobulin regulated by copper and iron availability | journal = The Journal of Nutritional Biochemistry | volume = 18 | issue = 9 | pages = 597–608 | date = September 2007 | pmid = 17363239 | pmc = 4286573 | doi = 10.1016/j.jnutbio.2006.11.005 }}</ref> 10 to 15% of copper in human plasma is chelated by α<sub>2</sub>-macroglobulin.<ref>{{cite journal | vauthors = Liu NM, Nguyen T, Kidane T, Moriya M, Goforth J, Chu A, Linder M | title = Transcupreins are serum copper-transporters of the macroglobulin family, and may be regulated by iron and copper | journal = The FASEB Journal | volume = 20 | issue = 4 | pages = A553–A554 | date = 6 March 2006 | doi = 10.1096/fasebj.20.4.A553-d | language = en | issn = 0892-6638 | s2cid = 90794136 | doi-access = free }}</ref>

==Disease==
α<sub>2</sub>-Macroglobulin levels are increased when the serum albumin levels are low,<ref>{{cite journal | vauthors = Stevenson F, Greene S, Kaysen G | title = Serum alpha 2-macroglobulin and alpha 1-inhibitor 3 concentrations are increased in hypoalbuminemia by post-transcriptional mechanisms. | journal = Kidney International | volume = 53 | issue = 1 | pages = 67–75 | date = January 1998 | pmid = 9453001 | doi = 10.1046/j.1523-1755.1998.00734.x | doi-access = free }}</ref> which is most commonly seen in [[nephrotic syndrome]], a condition wherein the [[kidney]]s start to leak out some of the smaller blood proteins. Because of its size, α<sub>2</sub>-macroglobulin is retained in the bloodstream. Increased production of all proteins means α<sub>2</sub>-macroglobulin concentration increases. This increase has little adverse effect on the health but is used as a diagnostic clue.

An increase in α<sub>2</sub>-Macroglobulin with normal amount of albumin mainly indicates acute and/or chronic inflammation.<ref>{{cite web | title = Protein electrophoresis - serum | url = https://www.mountsinai.org/health-library/tests/protein-electrophoresis-serum | website = Icahn School of Medicine at Mount Sinai }} Last reviewed on: 1/25/2022. Reviewed by: Todd Gersten, MD, and David Zieve, MD</ref>

A common variant (29.5%) ([[polymorphism (biology)|polymorphism]]) of α<sub>2</sub>-macroglobulin may lead to increased risk of [[Alzheimer's disease]].<ref name="Blacker_1998">{{cite journal | vauthors = 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 | title = Alpha-2 macroglobulin is genetically associated with Alzheimer disease | journal = Nature Genetics | volume = 19 | issue = 4 | pages = 357–360 | date = August 1998 | pmid = 9697696 | doi = 10.1038/1243 | s2cid = 15628847 }}</ref><ref name="Kovacs_2000">{{cite journal | vauthors = Kovacs DM | title = alpha2-macroglobulin in late-onset Alzheimer's disease | journal = Experimental Gerontology | volume = 35 | issue = 4 | pages = 473–479 | date = July 2000 | pmid = 10959035 | doi = 10.1016/S0531-5565(00)00113-3 | s2cid = 54409507 }}</ref> However, findings from meta-analyses have been inconclusive, and the association remains debated.<ref>{{Cite journal | vauthors = Li Z, liu N, Zhang W, Zhu G, Chen H | title = Influence of Alpha-2-Macroglobulin 5bp I/D and Ile1000Val Polymorphisms on the Susceptibility of Alzheimers disease: A Systematic Review and Meta-analysis of 52 Studies | journal = Cell Biochemistry and Biophysics | volume = 70 | issue = 1 | pages = 511–519 | date = 2014-09-01 | pmid = 24756728 | doi = 10.1007/s12013-014-9950-3 | url = https://link.springer.com/article/10.1007/s12013-014-9950-3 | language = en | issn = 1559-0283 | url-access = subscription }}</ref>

α<sub>2</sub>-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.

==References==
{{Reflist}}

==External links==
* The [[MEROPS]] online database for peptidases and their inhibitors: [https://archive.today/20121223112404/http://merops.sanger.ac.uk/cgi-bin/merops.cgi?id=I39.001 I39.001]
* {{MeshName|alpha+2-Macroglobulin}}
* {{UCSC genome browser|A2M}}   
* {{UCSC gene details|A2M}}


{{Alpha globulins}}
{{Acute phase proteins}}
{{Coagulation}}

[[Category:Acute-phase proteins]]