Alpha-2-Macroglobulin, a Hypochlorite-Regulated Chaperone and Immune System Modulator

Figure 1

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.