Ligand recognition specificity of leukocyte integrin αmβ2 (Mac-1, CD11b/CD18) and its functional consequences

Nataly Podolnikova, Andriy V. Podolnikov, Thomas A. Haas, Valeryi K. Lishko, Tatiana Ugarova

Research output: Contribution to journalArticlepeer-review

56 Scopus citations

Abstract

The broad recognition specificity exhibited by integrin αMβ2 (Mac-1, CD11b/CD18) has allowed this adhesion receptor to play innumerable roles in leukocyte biology, yet we know little about how and why αMβ2 binds its multiple ligands. Within αMβ2, the αMI-domain is responsible for integrin's multiligand binding properties. To identify its recognition motif, we screened peptide libraries spanning sequences of many known protein ligands for αMI-domain binding and also selected the αMI-domain recognition sequences by phage display. Analyses of >1400 binding and nonbinding peptides derived from peptide libraries showed that a key feature of the αMI-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 αMI-domain binding sites in the αMβ2 ligands. The recognition specificity of the αMI-domain resembles that of some chaperones, which allows it to bind segments exposed in unfolded proteins. The disclosure of the αMβ2 binding preferences allowed the prediction that cationic host defense peptides, which are strikingly enriched in the αMI-domain recognition motifs, represent a new class of αMβ2 ligands. This prediction has been tested by examining the interaction of αMβ2 with the human cathelicidin peptide LL-37. LL-37 induced a potent αMβ2-dependent cell migratory response and caused activation of αMβ2 on neutrophils. The newly revealed recognition specificity of αMβ2 toward unfolded protein segments and cationic proteins and peptides suggests that αMβ2 may serve as a previously proposed "alarmin" receptor with important roles in innate host defense.

Original languageEnglish (US)
Pages (from-to)1408-1420
Number of pages13
JournalBiochemistry
Volume54
Issue number6
DOIs
StatePublished - Feb 17 2015

ASJC Scopus subject areas

  • Biochemistry

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