CRYSTAL-STRUCTURE OF THE RECEPTOR-BINDING DOMAIN OF ALPHA(2)-MACROGLOBULIN

Background: The large plasma proteinase inhibitors of the alpha(2)-mac roglobulin superfamily inhibit proteinases by capturing-them within a central cavity of the inhibitor molecule. After reaction with the prot einase, the alpha-macroglobulin-proteinase complex binds to the alpha- macroglobulin receptor, present in the liver and other tissues, and be comes endocytosed and rapidly removed from the circulation. The comple x binds to the receptor via recognition sites located on a separate do main of approximately 138 residues positioned at the C terminus of the alpha-macroglobulin subunit. Results: The crystal structure of the re ceptor-binding domain of bovine alpha(2)-macroglobulin (bRBD) has been determined at a resolution of 1.9 Angstrom. The domain primarily comp rises a nine-strand beta structure with a jelly-roll topology, but als o contains two small alpha helices. Conclusions: The surface patch res ponsible for receptor recognition is thought to involve residues locat ed on one of the two alpha helices of the bRBD as well as residues in two of the beta strands. Located on this alpha helix are two lysine re sidues 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.