aMI-domain of Integrin Mac-1 Binds the Cytokine Pleiotrophin Using Multiple Mechanisms

The integrin Mac-1 (aMb2, 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 aMI-domain. However, the binding mechanism of most ligands is not clear. We have determined the interaction of aMI-domain with the cytokine pleiotrophin (PTN), a cationic protein known to bind aMI-domain and induce Mac-1-mediated cell adhesion and migration. Our data show that PTNs N-terminal domain binds a unique site near the N- and C-termini of the aMI-domain using a metal-independent mechanism. However, stronger interaction is achieved when an acidic amino acid in a zwitterionic motif in PTNs C-terminal domain chelates the divalent cation in the metal ion-dependent adhesion site of the active aMI-domain. These results indicate that aMI-domain can bind ligands using multiple mechanisms, and suggest that active aMI-domain prefers acidic amino acids in zwitterionic motifs. ### Competing Interest Statement The authors have declared no competing interest.