Protease-activated alpha-2-macroglobulin can inhibit amyloid formation via two distinct mechanisms

α₂-Macroglobulin (α₂M) is an extracellular chaperone that inhibits amorphous and fibrillar protein aggregation. The reaction of α₂M with proteases results in an 'activated' conformation, where the proteases become covalently-linked within the interior of a cage-like structure formed by α₂M. This study investigates, the effect of activation on the ability of α₂M to inhibit amyloid formation by Aβ_1-42 and I59T human lysozyme and shows that protease-activated α₂M can act via two distinct mechanisms: (i) by trapping proteases that remain able to degrade polypeptide chains and (ii) by a chaperone action that prevents misfolded clients from continuing along the amyloid forming pathway. Structured summary of protein interactions: Aβ_1-42 and Aβ_1-42 bind by fluorescence technology (View interaction)I59T lysozyme and I59T lysozyme bind by light scattering (View interaction)I59T lysozyme and I59T lysozyme bind by fluorescence technology (View interaction)Alpha-lactalbumin and Alpha-lactalbumin bind by fluorescence technology (View interaction)I59T lysozyme and I59T lysozyme bind by electron microscopy (View interaction)Aβ_1-42 and Aβ_1-42 bind by electron microscopy (View interaction).