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.
French
Katie
K
School of Biological Sciences, University of Wollongong, Northfields Avenue, Wollongong, NSW 2522, Australia.
Yerbury
Justin J
JJ
Wilson
Mark R
MR
D001665:Binding Sites; D004789:Enzyme Activation; D006358:Hot Temperature; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000378:metabolism; D018832:Molecular Chaperones / Q000378:metabolism*; D018384:Oxidative Stress; D010447:Peptide Hydrolases / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D011489:Protein Denaturation; D017510:Protein Folding; D012680:Sensitivity and Specificity; D014357:Trypsin / Q000378:metabolism; D000511:alpha-Macroglobulins / Q000737:chemistry / Q000378:metabolism*
D026502:LDL-Receptor Related Proteins; D018832:Molecular Chaperones; D000511:alpha-Macroglobulins; D010447:Peptide Hydrolases; D014357:Trypsin