Macroglobulin

Macroglobulin is a term used for high‑molecular‑weight plasma proteins that often function as protease inhibitors or carrier proteins. The best‑characterized human member is alpha-2-macroglobulin (A2M), a large, glycosylated protein secreted mainly by the liver into the bloodstream. A2M belongs to a family of macroglobulins distributed across vertebrates and tissues, and it participates in protease regulation and immune modulation.

Alpha-2-macroglobulin is a very large, tetrameric protein with a total molecular weight around 720 kDa. Its protease‑inhibitory mechanism involves a bait region that, when cleaved by proteases, triggers a conformational change in A2M that traps the protease inside the molecule. The resulting protease–A2M complex is then cleared from circulation by receptor-mediated endocytosis, primarily via LDL receptor–related protein 1 (LRP1). In addition to inhibiting proteases, A2M can bind and transport a range of cytokines, growth factors, and other signaling molecules, contributing to regulation of inflammation and tissue remodeling.

Clinical and physiological notes vary: plasma levels of A2M can change with inflammatory states and liver function, and measurement is not as routine as other acute‑phase proteins. It is important not to confuse macroglobulin with beta-2-microglobulin (β2M), a much smaller protein that is a component of MHC class I molecules and serves mainly as a clinical marker of renal function and certain diseases. The term macroglobulin is sometimes encountered in the context of macroglobulinemia, notably Waldenström’s macroglobulinemia, a monoclonal gammopathy of the IgM type.