Alpha2-macroglobulin (alpha2M) and related proteins share the function of binding host or foreign peptides and particles, thereby serving as humoral defense barriers against pathogens in the plasma and tissues of vertebrates. In human alpha2M, several reactive sites including high-affinity sites for zinc, transglutaminase cross-linking sites, and reactive sites derived from the activated thiol ester can mediate reversible or irreversible capture of proteins of diverse biological functions. Alpha2M interacts and captures virtually any proteinase whether self or foreign, suggesting a function as a unique "panproteinase inhibitor." Activation of alpha2M generates novel binding sites, which mediate complex formation with cytokines and other peptides. Direct evidence of physical association of cytokines with activated alpha2M indicated its role as biological response modifier in cell cultures. A mechanism commonly referred to as "clearance of activated alpha2M" involves Ca2+-dependent binding to a specific cell surface receptor, a member of the low-density lipoprotein receptor supergene family, that mediates cellular uptake by endocytosis and delivery to endosomes and lysosomes. The peptide binding function of alpha2M, therefore, may also be viewed as a mechanism that allows targeting of biologically active peptides to different cell types expressing the alpha2M receptor. Internalized complexes may be dispatched into different pathways of endocytic/lysosomal pathways in a cell type-specific manner. In addition, bioactive peptides bound to alpha2M may dissociate in the process of intracellular ligand sorting, thereby modulating cell function, or remain bound and share the catabolic fate of alpha2M. The diversified and probably programmed binding functions of alpha2M indicate that in addition to its role in trapping proteinases, it has other biological activities that remain to be fully defined. That alpha2M may function as a binding and carrier protein with targeting characteristics is predicted from 1) the known functions of alpha2M, and 2) the similarity of the fate of alpha2M with proteins whose significance in targeting and intracellular trafficking has been studied in more detail.
