View source for Alpha-2-Macroglobulin

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'''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]].

== Structure ==

Human alpha-2-macroglobulin is composed of four identical subunits bound together by -S-S- bonds.<ref name="pmid7559647">{{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 = J. Biol. Chem. | volume = 270 | issue = 42 | pages = 25133–41 |date=October 1995 | pmid = 7559647 | doi = 10.1074/jbc.270.42.25133| url = | issn = }}</ref><ref name="pmid6203908">{{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=J Biol Chem | year= 1984 | volume= 259 | issue= 13 | pages= 8318–27 | pmid=6203908 | doi= | pmc= | url= |display-authors=etal}}</ref> In addition to tetrameric forms of alpha-2-macroglobulin, dimeric, and more recently monomeric aM protease inhibitors have been identified.<ref name="pmid9914899">{{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 = Immunol. Rev. | volume = 166 | issue = | pages = 15–26 |date=December 1998 | pmid = 9914899 | doi = 10.1111/j.1600-065X.1998.tb01249.x | url = }}</ref><ref name="pmid10426429">{{cite journal | vauthors = Armstrong PB, Quigley JP | title = Alpha2-macroglobulin: an evolutionarily conserved arm of the innate immune system | journal = Dev. Comp. Immunol. | volume = 23 | issue = 4-5 | pages = 375–90 | year = 1999 | pmid = 10426429 | doi = 10.1016/s0145-305x(99)00018-x| url = }}</ref>

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.<ref name="pmid17608619">{{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=Biochem J | year= 2007 | volume= 407 | issue= 1 | pages= 23–30 | pmid=17608619 | doi=10.1042/BJ20070764 | pmc=2267405 }}</ref> Overall, alpha-2-Macroglobulin is the largest major nonimmunoglobulin protein in human plasma.

== Function ==

The alpha-macroglobulin (aM) [[protein family|family of proteins]] includes [[protease inhibitor (biology)|protease inhibitor]]s,<ref name="pmid2473064">{{cite journal | author = Sottrup-Jensen L | title = Alpha-macroglobulins: structure, shape, and mechanism of proteinase complex formation | journal = J. Biol. Chem. | volume = 264 | issue = 20 | pages = 11539–42 |date=July 1989 | pmid = 2473064 | doi = | url = }}</ref> typified by the [[Homo sapiens|human]] [[tetrameric protein|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 [[Enzyme inhibitor|inhibit]] [[protease]]s 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 [[amine]]s. aM [[Protease inhibitor (biology)|protease inhibitor]]s inhibit by [[steric]] hindrance.<ref name="pmid2472396">{{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 = J. Biol. Chem. | volume = 264 | issue = 19 | pages = 11428–35 |date=July 1989 | pmid = 2472396 | doi = | url = }}</ref> The [[Nuclear receptor#Mechanism of action|mechanism]] involves protease [[Bond cleavage|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 [[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 (i) the h-cysteinyl-g-glutamyl thiol ester becomes highly reactive and (ii) a major [[Protein structure|conformational]] change exposes a [[conserved sequence|conserved]] COOH-terminal [[receptor (biochemistry)|receptor]] [[Binding (molecular)|binding]] domain <ref name="pmid2469470">{{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 = 1406–12 |date=February 1989 | pmid = 2469470 | doi = 10.1021/bi00429a069| url = }}</ref> (RBD). RBD exposure allows the aM protease [[Protein complex|complex]] to [[Molecular binding|bind]] to clearance [[Receptor (biochemistry)|receptors]] and be removed from circulation.<ref name="pmid2430968">{{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 = J. Biol. Chem. | volume = 261 | issue = 35 | pages = 16622–5 |date=December 1986 | pmid = 2430968 | doi = | url = }}</ref> Tetrameric, dimeric, and, more recently, monomeric aM protease inhibitors have been identified.<ref name="pmid9914899" /><ref name="pmid10426429" />

alpha-2-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="pmid7693593">{{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 = Infect. Immun. | volume = 61 | issue = 12 | pages = 5035–43 |date=December 1993 | pmid = 7693593 | pmc = 281280 | doi = | url = | issn = }}</ref> 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.

[[Image:Fibrinolysis.png|center|framed|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'''.<ref>{{cite journal|last1=Liu|first1=Nanmei|last2=Lo|first2=Louis Shi-li|last3=Askary|first3=S. Hassan|last4=Jones|first4=LaTrice|last5=Kidane|first5=Theodros Z.|last6=Nguyen|first6=Trisha Trang Minh|last7=Goforth|first7=Jeremy|last8=Chu|first8=Yu-Hsiang|last9=Vivas|first9=Esther|last10=Tsai|first10=Monta|last11=Westbrook|first11=Terence|last12=Linder|first12=Maria C.|title=Transcuprein is a macroglobulin regulated by copper and iron availability|journal=The Journal of Nutritional Biochemistry|date=September 2007|volume=18|issue=9|pages=597–608|doi=10.1016/j.jnutbio.2006.11.005}}</ref> 10-15% of copper in human plasma is chelated by alpha-2-macroglobulin.<ref>{{cite journal|last1=Liu|first1=Nan-mei|last2=Nguyen|first2=Trang|last3=Kidane|first3=Theodros|last4=Moriya|first4=Mizue|last5=Goforth|first5=Jeremy|last6=Chu|first6=Andy|last7=Linder|first7=Maria|title=Transcupreins are serum copper-transporters of the macroglobulin family, and may be regulated by iron and copper|journal=The FASEB Journal|date=6 March 2006|volume=20|issue=4|pages=A553–A554|url=http://www.fasebj.org/content/20/4/A553.5.short|language=en|issn=0892-6638}}</ref>

== Disease ==

alpha-2-Macroglobulin levels are increased when the serum albulin levels are low,<ref>{{cite journal|last1=Stevenson|first1=FT|last2=Greene|first2=S|last3=Kaysen|first3=GA|title=Serum alpha 2-macroglobulin and alpha 1-inhibitor 3 concentrations are increased in hypoalbuminemia by post-transcriptional mechanisms.|journal=Kidney International|date=January 1998|volume=53|issue=1|pages=67–75|doi=10.1046/j.1523-1755.1998.00734.x|pmid=9453001}}</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, 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 (biology)|polymorphism]]) of alpha-2-macroglobulin leads to increased risk of [[Alzheimer's disease]].<ref name="pmid9697696">{{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 = Nat. Genet. | volume = 19 | issue = 4 | pages = 357–60 |date=August 1998 | pmid = 9697696 | doi = 10.1038/1243 | url = | issn = }}</ref><ref name="pmid10959035">{{cite journal | author = Kovacs DM | title = alpha2-macroglobulin in late-onset Alzheimer's disease | journal = Exp. Gerontol. | volume = 35 | issue = 4 | pages = 473–9 |date=July 2000 | pmid = 10959035 | doi = 10.1016/S0531-5565(00)00113-3 | url = | issn = }}</ref>

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.

== References ==
{{Reflist|30em}}
* McPherson & Pincus: Henry's Clinical Diagnosis and Management by Laboratory Methods, 21st ed.
* Firestein: Kelley's Textbook of Rheumatology, 8th edition.

== External links ==
* The [[MEROPS]] online database for peptidases and their inhibitors: [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]]