title: Integrin alphaDbeta2, an adhesion receptor up-regulated on macrophage foam cells, exhibits multiligand-binding properties.
abstract: Integrin alphaDbeta2, the most recently discovered member of the beta2 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 alphaDbeta2 ligand binding remain unknown. Based on the high extent of structural homology between alphaDbeta2 and the major myeloid-cell-specific integrin alphaMbeta2 (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 alphaDbeta2-expressing cells, we demonstrate that alphaDbeta2 supports adhesion and migration to many extracellular matrix proteins in a fashion similar to alphaMbeta2. Consistent with these data, the recombinant alphaDI-domain of the receptor bound selected ligands. The binding was activation-dependent because the alphaDI-domain with its C-terminal alpha7 helix truncated, but not the form with the C-terminal part extended, bound ligands. When the alphaDI-domain segment Lys244-Lys260 (highly homologous to its alphaMI-domain counterpart Lys245-Arg261 responsible for alphaMbeta2 multiligand-binding properties) was inserted into the mono-specific alphaLI-domain, the chimeric protein bound many ligands with affinities similar to those of wild-type alphaDI-domain. These results establish integrin alphaDbeta2 as a multiligand receptor and indicate that the mechanism whereby alphaDbeta2 exhibits broad ligand specificity resembles that used by alphaMbeta2, the most promiscuous member of the integrin family.
authors.affiliation: Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic Foundation, OH 44195, USA.
authors.forename: Valentin P
authors.initials: VP
authors.lastname: Yakubenko
authors.forename: Satya P
authors.initials: SP
authors.lastname: Yadav
authors.forename: Tatiana P
authors.initials: TP
authors.lastname: Ugarova
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D018845:CD11 Antigens / Q000235:genetics* / Q000378:metabolism; D005487:Foam Cells / Q000502:physiology*; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D039001:Integrin alpha Chains / Q000235:genetics* / Q000378:metabolism; D008024:Ligands; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry
chemical_list: D018845:CD11 Antigens; C406812:ITGAD protein, human; D039001:Integrin alpha Chains; D008024:Ligands; D010446:Peptide Fragments