Integrin D 2 , an adhesion receptor up - regulated on macrophage foam cells , exhibits multiligand - binding properties

Integrin D 2, the most recently discovered member of the 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 D 2 ligand binding remain unknown. Based on the high extent of structural homology between D 2 and the major myeloid-cell–specific integrin M 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 D 2-expressing cells, we demonstrate that D 2 supports adhesion and migration to many extracellular matrix proteins in a fashion similar to M 2. Consistent with these data, the recombinant DI-domain of the receptor bound selected ligands. The binding was activation-dependent because the DIdomain with its C-terminal 7 helix truncated, but not the form with the Cterminal part extended, bound ligands. When the DI-domain segment Lys244Lys260 (highly homologous to its MIdomain counterpart Lys245-Arg261 responsible for M 2 multiligand-binding properties) was inserted into the monospecific LI-domain, the chimeric protein bound many ligands with affinities similar to those of wild-type DI-domain. These results establish integrin D 2 as a multiligand receptor and indicate that the mechanism whereby D 2 exhibits broad ligand specificity resembles that used by M 2, the most promiscuous member of the integrin family. (Blood. 2006;107: 1643-1650)