α2-Macroglobulin (α2M) oralpha-2-macroglobulin is a large (720 KDa)plasma protein found in theblood. It is mainly produced by theliver, and also locally synthesized bymacrophages,fibroblasts, andadrenocortical cells. In humans it is encoded by theA2M 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 inhibitingplasmin andkallikrein. It functions as an inhibitor of coagulation by inhibitingthrombin. 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 maintainingoncotic pressure.
Human α2-macroglobulin is composed of four identical subunits bound together by-S-S- bonds.[5][6] In addition totetrameric forms of α2-macroglobulin,dimeric, and more recentlymonomeric 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.
Theamino acid sequence of α2-macroglobulin has been shown to be 71% the same as that of thepregnancy zone protein (PZP; also known as pregnancy-associated α2-glycoprotein).[10]
Theα-macroglobulin (αM)family of proteins includesprotease inhibitors,[11] typified by thehumantetrameric α2-macroglobulin (α2M); they belong to the MEROPSproteinase inhibitor family I39, clan IL. These protease inhibitors share several defining properties, which include (1) the ability toinhibitproteases from allcatalytic classes, (2) the presence of a 'bait region' (also known as a sequence ofamino acids in an α2-macroglobulin molecule, or a homologous protein, that contains scissile peptide bonds for those proteinases that it inhibits) and athiol ester, (3) a similar protease inhibitory mechanism and (4) the inactivation of the inhibitory capacity by reaction of the thiolester with small primaryamines. αMprotease inhibitors inhibit bysteric hindrance.[12] Themechanism involves proteasecleavage of the bait region, a segment of the αM that is particularly susceptible toproteolytic cleavage, which initiates aconformational change such that the αM collapses about the protease. In the resulting αM-protease complex, theactive site of the protease issterically shielded, thus substantially decreasing access toproteinsubstrates. 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 majorconformational change exposes aconservedCOOH-terminalreceptorbinding domain[13] (RBD). RBD exposure allows the αM proteasecomplex tobind to clearancereceptors 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 (includingserine-,cysteine-,aspartic- andmetalloproteinases). It functions as an inhibitor offibrinolysis by inhibitingplasmin and kallikrein. It functions as an inhibitor ofcoagulation by inhibitingthrombin.[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 bindzinc, as well ascopper in plasma, even more strongly than albumin, and such it is also known astranscuprein.[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 innephrotic syndrome, a condition wherein thekidneys 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 may lead to increased risk ofAlzheimer's disease.[20][21] However, findings from meta-analyses have been inconclusive, and the association remains debated.[22]
α2-Macroglobulin binds to and removes the active forms of thegelatinase (MMP-2 andMMP-9) from the circulation via scavenger receptors on the phagocytes.
