Schematic diagram showing the function consequences of hypochlorite-induced modification of α2M. (a) Native α2M, a tetramer (shown in green), is constitutively present in biological fluids and covalently binds to a broad range of proteases. Binding to proteases results in a conformational change that exposes the binding site on α2M for LRP1, which is responsible for the clearance of the protease-transformed α2M complex (shown in dark blue). α2M also binds to a large number of noncovalent ligands including cytokines and misfolded proteins. In many cases, noncovalent binding of ligands occurs preferentially to the protease-transformed conformation (not shown). In the instance that native α2M binds noncovalently to a nonprotease substrate, protease interaction is required to enable clearance of the complex via LRP1. (b) Reaction with hypochlorite induces the dissociation of the native α2M tetramer into dimers. This process abolishes the protease-trapping activity of α2M; however, the binding to some cytokines (i.e., TNF-α, IL-2, and IL-6) and misfolded proteins is enhanced. On the other hand, the binding of α2M to other noncovalent ligands (i.e., β-NGF, PDGF-BB, TGF-β1, and TGF-β2) is reduced. The dissociation of the native α2M tetramer into dimers reveals the binding site on α2M for LRP1. Therefore, α2M dimers can facilitate the clearance of substrates in a protease-independent manner. N.B.: Inflammatory processes potentially elevate levels of protease-transformed α2M and hypochlorite-modified α2M dimers, concomitantly.