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

Nataly P. Podolnikova, Andriy V. Podolnikov, Thomas A. Haas, Valeryi K. Lishko, Tatiana P. Ugarova
2015 Biochemistry  
The broad recognition specificity exhibited by integrin  M  2 (Mac-1, CD11b/CD18) has allowed this adhesion receptor to play innumerable roles in leukocyte biology, yet we know little how and why  M  2 binds its multiple ligands. Within  M  2 , the  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  M I-domain binding and also selected the  M
more » ... I-domain recognition sequences by phage display. Analyses of >1400 binding and nonbinding peptides derived from peptide libraries showed that a key feature of the  M I-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 which reliably predicts the  M Idomain binding sites in the  M  2 ligands. The recognition specificity of the  M I-domain resembles that of some chaperones which enables it to bind segments exposed in unfolded proteins. The disclosure of the  M  2 binding preferences allowed the prediction that cationic host defense peptides, which are strikingly enriched in the  M I-domain recognition motifs, represent a new class of  M  2 ligands. This prediction has been tested by examining the interaction of  M  2 with the human cathelicidin peptide LL-37. LL-37 induced a potent  M  2 -dependent cell migratory response and caused activation of  M  2 on neutrophils. The newly revealed recognition specificity of  M  2 towards unfolded protein segments and cationic proteins/peptides suggests that  M  2 may serve as a previously proposed "alarmin" receptor with important roles in innate host defense.
doi:10.1021/bi5013782 pmid:25613106 pmcid:PMC4532391 fatcat:mi6ntjyms5b3fiicx2rb4hxd5i