Macroglobulins (Molecular Biology)

Macroglobulins are large glycoproteins found in the circulation of vertebrates and invertebrates. They are also present in bird and reptile egg whites. When appropriately triggered, macroglobulins become binding proteins for proteinases belonging to all four mechanistic classes [see Proteinase Inhibitors, Protein]. In macroglobulin-proteinase complexes, the active site of the enzyme is generally left open and active. Some complexes are slightly more active, others slightly less active, toward small substrates than these enzymes. They can still be inhibited by small inhibitors. It is the interaction with large substrates that is prevented in complexes.

Complex formation starts by a specific cleavage of a peptide bond in the bait region of macroglobulin. However, in contrast to the single reactive site peptide bonds of protein serine proteinase inhibitors [see Serine proteinase inhibitors], one of many different peptide bonds can be broken to trigger. These accommodate the specificity of many different proteinases, so that macroglobulins are panspecific and "inhibit" most, but not all, proteinases. When elimination of action toward large substrates suffices, macroglobulins are the best choice to cut down on proteolysis by poorly understood or poorly characterized enzymes. After the bait region is triggered, the macroglobulin undergoes a conformational change that traps the enzyme molecule(s). In many macroglobulins, this noncovalent trapping is followed by formation of isopeptide bonds between the macroglobulin and the enzyme. The macroglobulins that undergo this reaction contain in them the sequence^Cys Gly Glu GlnHwhich leads to the formation of an internal thioester bond between the Cys and Gln residues (with the release of NH3). The thioester then reacts with Lys residues of the trapped enzyme to form isopeptide bonds.

The most studied of macroglobulins is human a 2macroglobulin, which is a homotetramer of four chains, each of 1451 amino acid residues. It is a noncovalent homodimer of two disulfide bridged homodimers. It forms isopeptide bonds with trapped enzymes. Potentially, it has two enzyme binding sites, but whether one or two will be employed depends strongly on the kinetics of binding.

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