α(M)I-domain of Integrin Mac-1 Binds the Cytokine Pleiotrophin Using Multiple Mechanisms.

The integrin Mac-1 (α(M)β(2), CD11b/CD18, CR3) is an important adhesion receptor expressed on macrophages and neutrophils. Mac-1 is also the most promiscuous member of the integrin family that binds a diverse set of ligands through its α(M)I-domain. However, the binding mechanism of most ligands is not clear. We have determined the interaction of α(M)I-domain with the cytokine pleiotrophin (PTN), a cationic protein known to bind α(M)I-domain and induce Mac-1-mediated cell adhesion and migration. Our data show that PTN's N-terminal domain binds a unique site near the N- and C-termini of the α(M)I-domain using a metal-independent mechanism. However, stronger interaction is achieved when an acidic amino acid in a zwitterionic motif in PTN's C-terminal domain chelates the divalent cation in the metal ion-dependent adhesion site of the active α(M)I-domain. These results indicate that α(M)I-domain can bind ligands using multiple mechanisms, and suggest that active α(M)I-domain prefers acidic amino acids in zwitterionic motifs.