Alpha-2-Macroglobulin

alpha-2-Macroglobulin, also known as α₂-macroglobulin and abbreviated as α2M and A2M, is a large plasma protein found in the blood. It is produced by the liver, and is a major component of the alpha-2 band in protein electrophoresis.

Structure

Alpha-2-macroglobulin is compose of four identical subunits bound together by -S-S- bonds.

Function

Alpha-2-macroglobulin is able to inactivate an enormous variety of proteinases (including serine-, cysteine-, aspartic- and metalloproteinases).

Alpha-2-macroglobulin has in its structure a 35 aminoacid "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.

It functions as an inhibitor of coagulation by inhibiting thrombin. [Boer JP, Creasey AA, Chang A, Abbink JJ, "et al". (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): 5035–5043.]

It functions as an inhibitor of fibrinolysis by inhibiting plasmin and kallikrein

Disease

Alpha-2-macroglobulin levels are increased 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. Longstanding chronic renal failure can lead to amyloid by "alpha-2-macroglobulin" ("see main article: amyloid").

A common variant (29.5%) (polymorphism) of α2-macroglobulin leads to increased risk of Alzheimer's disease, [cite journal | author=Blacker D, Wilcox MA, Laird NM, "et al." | title=Alpha-2-macroglobulin is genetically associated with Alzheimer disease | journal=Nat Genet | year=1998 | volume=19| issue=4 | pages=357–60 | pmid=9697696 | doi=10.1038/1243] [cite journal | author=Kovacs DM | journal=Exp Gerontol | year=2000 | volume=35 | issue=4 | pages=473–9 | title=alpha2-macroglobulin in late-onset Alzheimer's disease | pmid=10959035 | doi=10.1016/S0531-5565(00)00113-3] although the mechanism is unknown.

α-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

4. G.R. Andersen, T.J. Koch, K. Dolmer, L. Sottrup-Jensen and J. Nyborg, Low resolution X-ray structure of human methylamine-treated alpha 2-macroglobulin, J. Biol. Chem. 270 (1995), pp. 25133–25141.

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