InterPro domain: IPR001599

This entry contains serum complement C3 and C4 precursors and alpha-macrogrobulins.

The alpha-macroglobulin (aM) family of proteins includes protease inhibitors [ 1 ], typified by the human tetrameric a2-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 inhibit proteases from all catalytic classes, (ii) the presence of a 'bait region' and a thiol ester, (iii) a similar protease inhibitorymechanism and (iv) the inactivation of the inhibitory capacity by reaction of the thiol ester with small primary amines. aM protease inhibitors inhibit by steric hindrance [ 2 ]. The mechanism involves protease 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 sterically shielded, thus substantially decreasing access to protein 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 conformational change exposes a conserved COOH-terminal receptor binding domain [ 3 ] (RBD). RBD exposure allows the aM protease complex to bind to clearance receptors and be removed from circulation [ 4 ]. Tetrameric, dimeric, and, more recently, monomeric aM protease inhibitors have been identified [ 5 , 6 ].

1. Alpha-macroglobulins: structure, shape, and mechanism of proteinase complex formation. J. Biol. Chem. 264, 11539-42
2. Proteinase binding and inhibition by the monomeric alpha-macroglobulin rat alpha 1-inhibitor-3. J. Biol. Chem. 264, 11428-35
3. A conserved region in alpha-macroglobulins participates in binding to the mammalian alpha-macroglobulin receptor. Biochemistry 28, 1406-12
4. Human pregnancy zone protein and alpha 2-macroglobulin. High-affinity binding of complexes to the same receptor on fibroblasts and characterization by monoclonal antibodies. J. Biol. Chem. 261, 16622-5
5. The phylogeny and evolution of the thioester bond-containing proteins C3, C4 and alpha 2-macroglobulin. Immunol. Rev. 166, 15-26
6. Alpha2-macroglobulin: an evolutionarily conserved arm of the innate immune system. Dev. Comp. Immunol. 23, 375-90