Protease activation of alpha2-macroglobulin modulates a chaperone-like action with broad specificity.

Alpha2-macroglobulin (alpha2M) 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 alpha2M with an exposed binding site for the low-density lipoprotein receptor, facilitating clearance of alpha2M/protease complexes from the body. This report establishes that protease activation also modulates a potent chaperone-like action of alpha2M that has broad specificity for proteins partly unfolded as a result of heat or oxidative stress. Protease-mediated activation of alpha2M abolishes its chaperone-like activity. However, native alpha2M 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 alpha2M/stressed protein/protease complexes. We propose that alpha2M 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.