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

α(2)-Macroglobulin (α(2)M) is an extracellular chaperone that inhibits amorphous and fibrillar protein aggregation. The reaction of α(2)M with proteases results in an ‘activated’ conformation, where the proteases become covalently-linked within the interior of a cage-like structure formed by α(2)M. This study investigates, the effect of activation on the ability of α(2)M to inhibit amyloid formation by Aβ(1–42) and I59T human lysozyme and shows that protease-activated α(2)M 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)