Protease activation of α2-Macroglobulin modulates a chaperone-like action with broad specificity

alpha(2)-Macroglobulin (alpha M-2) is a major human blood glycoprotein best known for its ability to inhibit a broad spectrum of proteases by a unique trapping method. This action induces an activated conformation of alpha M-2 with an exposed binding site for the low-density lipoprotein receptor, facilitating clearance of alpha M-2/protease complexes from the body. This report establishes that protease activation also modulates a potent chaperone-like action of alpha M-2 that has broad specificity for proteins partly unfolded as a result of heat or oxidative stress. Protease-mediated activation of alpha M-2 abolishes its chaperone-like activity. However, native alpha M-2 is able to form soluble complexes with stressed proteins and then subsequently become activated by interacting with a protease, providing a potential mechanism for the in vivo clearance of alpha M-2/stressed protein/protease complexes. We propose that alpha M-2 is a newly discovered and unique member of a small group of abundant extracellular proteins with chaperone properties that patrol extracellular spaces for unfolded/misfolded proteins and facilitate their disposal.