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

alpha(2)-Macroglobulin (alpha M-2) is an extracellular chaperone that inhibits amorphous and fibrillar protein aggregation. The reaction of alpha M-2 with proteases results in an 'activated' conformation, where the proteases become covalently-linked within the interior of a cage-like structure formed by alpha M-2. This study investigates, the effect of activation on the ability of alpha M-2 to inhibit amyloid formation by A beta(1-42) and I59T human lysozyme and shows that protease-activated alpha M-2 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: A beta(1-42) and A beta(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) A beta(1-42) and A beta(1-42) bind by electron microscopy (View interaction) (C) 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.