Crystal structure of the receptor-binding domain of α2-macroglobulin

AbstractBackground: The large plasma proteinase inhibitors of the α2-macroglobulin superfamily inhibit proteinases by capturing them within a central cavity of the inhibitor molecule. After reaction with the proteinase, the α-macroglobulin–proteinase complex binds to the α-macroglobulin receptor, present in the liver and other tissues, and becomes endocytosed and rapidly removed from the circulation. The complex binds to the receptor via recognition sites located on a separate domain of approximately 138 residues positioned at the C terminus of the α-macroglobulin subunit.Results: The crystal structure of the receptor-binding domain of bovine α2-macroglobulin (bRBD) has been determined at a resolution of 1.9 å. The domain primarily comprises a nine-strand β structure with a jelly-roll topology, but also contains two small α helices.Conclusions: The surface patch responsible for receptor recognition is thought to involve residues located on one of the two α helices of the bRBD as well as residues in two of the β strands. Located on this α helix are two lysine residues that are important for receptor binding. The structure of bRBD is very similar to the approximately 100-residue C-terminal domain of factor XIII, a transglutaminase from the blood coagulation system