Structure of a rat α1-macroglobulin receptor-binding domain dimer

alpha -Macroglobulin inhibits a broad spectrum of proteinases by forming macromolecular cages inside which proteinases are cross-linked and trapped. Upon formation of a complex with proteinase. alpha -macroglobulin undergoes a large conformational change that results in the exposure of its receptor-binding domain (RBD). Engagement of this domain by alpha -macroglobulin receptor permits clearance of the alpha -macroglobulin: proteinase complex from circulation. The crystal structure of rat alpha (1)-macroglobulin RED has been determined at 2.3 Angstrom resolution. The RED is composed of a nine-stranded beta -sandwich and a single alpha -helix that has been implicated as part of the receptor binding site and that lies on the surface of the beta -sandwich. The crystallographic asymmetric unit contains a dimer of RBDs related by approximate twofold symmetry such that the putative receptor recognition sites of the two monomers are contiguous. By gel Filtration and ultracentrifugation, it is shown that RED dimers form in solution with a dissociation constant of similar to 50 muM. The structure of the RED dimer might mimic a conformation of transformed alpha -macroglobulin in which the proposed receptor binding residues are exposed on one face of the dimer. A pair of phenylalanine residues replaces a cystine that is conserved in other members of the macroglobulin family. There residues participate in a network of aromatic side-chain interactions that appears to stabilize the dimer interface.