Recognition Specificity of Leukocyte Integrin α M β 2 (Mac‐1, CD11b/CD18) and its Functional Consequences

The broad recognition specificity exhibited by integrin α M β 2 has allowed this adhesion receptor to play innumerable roles in leukocyte biology, yet we know little how and why α M β 2 binds its ligands. Within α M β 2 , the α M I‐domain is responsible for integrin's multiligand binding properties. To determine its recognition motif, we screened peptide libraries spanning sequences of many known protein ligands for the α M I‐domain binding and also selected the α M I‐domain recognition sequences by phage display. A key feature of the α M I‐domain recognition motif is a small core consisting of basic amino acids flanked by hydrophobic residues. Identification of the motif allowed the construction of an algorithm which reliably predicts the α M I‐domain binding sites in the α M β 2 ligands. The recognition specificity of the α M I‐domain resembles that of some chaperones which enables it to bind segments exposed by protein denaturation. The disclosure of the α M β 2 binding preferences allowed the prediction that cationic host defense peptides, which are strikingly enriched in the a M I‐domain recognition motifs, represent a new class of α M β 2 ligands. This prediction has been tested by examining the interaction of α M β 2 with the human cathelicidin peptide LL‐37. LL‐37 induced a potent α M β 2 ‐dependent cell migratory response, caused activation of α M β 2 on neutrophils and α M β 2 ‐mediated signaling in monocytes. The newly revealed recognition specificity of α M β 2 towards unfolded protein segments and cationic proteins/peptides suggests that α M β 2 may serve as a previously proposed “alarmin” receptor with important roles in innate host defense. NIH HL 63199