Integrin αDβ2, an adhesion receptor up-regulated on macrophage foam cells, exhibits multiligand-binding properties

Integrin alpha(D)beta(2), the most recently discovered member of the beta(2) subfamily of integrin adhesion receptors, is up-regulated on macrophage foam cells. Although other members of the subfamily have been subjects of extensive research, the recognition specificity and the molecular basis for alpha(D)beta(2) ligand binding remain unknown. Based on the high extent of structural homology between alpha(D)beta(2) and the major myeloid-cell-specific integrin alpha(M)beta(2) (Mac-1), noted for its capacity to bind multiple ligands, we considered that the 2 integrins have similar recognition specificity. In this study, using recombinant and natural alpha(D)beta(2)-expressing cells, we demonstrate that alpha(D)beta(2) supports adhesion and migration to many extracellular matrix proteins in a fashion similar to OWN. Consistent with these data, the recombinant alpha I-D-domain of the receptor bound selected ligands. The binding was activation-dependent because the UDI-domain with its C-terminal alpha 7 helix truncated, but not the form with the C-terminal part extended, bound ligands. When the UDI-domain segment Lys(244)-Lys(260) (highly homologous to its alpha(M)l-domain counterpart Lys(245)-Arg(261) responsible for alpha(M)beta(2) multiligand-binding and natural alpha(D)beta(2)-expressing cells, we demonstrate that alpha(D)beta(2) supports adhesion and migration to many extracellular matrix proteins in a fashion similar to OWN. Consistent with these data, the recombinant alpha(D)l-domain of the receptor bound selected ligands. The binding was activation-dependent because the UDI-domain with its C-terminal alpha 7 helix truncated, but not the form with the C-terminal part extended, bound ligands. When the UDI-domain segment Lys(244)-Lys(260) (highly homologous to its alpha(M)l-domain counterpart Lys(245)-Arg(261) responsible for alpha(M)beta(2) multiligand-binding and natural alpha(D)beta(2)-expressing cells, we demonstrate that alpha(D)beta(2) supports adhesion and migration to many extracellular matrix proteins in a fashion similar to OWN. Consistent with these data, the recombinant alpha DI-domain of the receptor bound selected ligands. The binding was activation-dependent because the UDI-domain with its C-terminal alpha 7 helix truncated, but not the form with the C-terminal part extended, bound ligands. When the UDI-domain segment Lys(244)-Lys(260) (highly homologous to its alpha(M)l-domain counterpart Lys(245)-Arg(261) responsible for alpha(M)beta(2) multiligand-binding properties) was inserted into the monospecific alpha(L)l-domain, the chimeric protein bound many ligands with affinities similar to those of wild-type alpha(D)l-domain. These results establish integrin alpha(D)beta(2) as a multiligand receptor and indicate that the mechanism whereby alpha(D)beta(2) exhibits broad ligand specificity resembles that used by OWN, the most promiscuous member of the integrin family.