Ligand Recognition Specificity of Leukocyte Integrin αMβ2 (Mac-1, CD11b/CD18) and Its Functional Consequences

The broad recognition specificity exhibited by integrin alpha(M)beta(2) (Mac-1, CD11b/CD18) has allowed this adhesion receptor to play innumerable roles in leukocyte biology, yet we know little about how and why alpha(M)beta(2) binds its multiple ligands. Within alpha(M)beta(2), the alpha I-M-domain is responsible for integrins multiligand binding properties. To identify its recognition motif, we screened peptide libraries spanning sequences of many known protein ligands for alpha I-M-domain binding and also selected the alpha I-M-domain recognition sequences by phage display. Analyses of >1400 binding and nonbinding peptides derived from peptide libraries showed that a key feature of the alpha I-M-domain recognition motif is a small core consisting of basic amino acids flanked by hydrophobic residues. Furthermore, the peptides selected by phage display conformed to a similar pattern. Identification of the recognition motif allowed the construction of an algorithm that reliably predicts the alpha I-M-domain binding sites in the alpha(M)beta(2) ligands. The recognition specificity of the alpha I-M-domain resembles that of some chaperones, which allows it to bind segments exposed in unfolded proteins. The disclosure of the alpha(M)beta(2) binding preferences allowed the prediction that cationic host defense peptides, which are strikingly enriched in the alpha I-M-domain recognition motifs, represent a new class of alpha(M)beta(2) ligands. This prediction has been tested by examining the interaction of alpha(M)beta(2) with the human cathelicidin peptide LL-37. LL-37 induced a potent alpha(M)beta(2)-dependent cell migratory response and caused activation of alpha(M)beta(2) on neutrophils. The newly revealed recognition specificity of alpha(M)beta(2) toward unfolded protein segments and cationic proteins and peptides suggests that alpha(M)beta(2) may serve as a previously proposed alarmin receptor with important roles in innate host defense.