Alpha 2-macroglobulin (A2M) is a plasma glycoprotein consisting of 4 near-identical subunits (Andersen et al. 1995). A2M inhibits almost all endopeptidases regardless of their specificities (Barrett 1981). A2M binding to an endopeptidase is triggered by cleavage of a peptide bond in the 'bait region' of A2M, triggering a conformational change in A2M that in turn entraps the peptidase without blocking the active site (Barrett & Starkey 1973). This blocks enzyme activity against large protein substrates while not preventing activity on low molecular weight substrates.

Once bound, A2M-proteinase complexes are endocytosed by low density lipoprotein receptor-related protein-1 (LRP1) (Strickland et al. 1990).

Active metalloproteinases (MMPs) that can be entrapped by A2M include MMP3 (Enghild et al. 1989) MMP1 (Grinnell et al. 1998) and MMP 13 (Beekman et al. 1999).

The significance of this mechanism as a regulator of MMP activity is unclear (Baker et al. 2002, Nagase et al. 2006).