Ligand Recognition Specificity of Leukocyte Integrin 伪M尾2 (Mac-1, CD11b/CD18) and Its Functional Consequences

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• 作者：Nataly P. Podolnikova ; Andriy V. Podolnikov ; Thomas A. Haas ; Valeryi K. Lishko ; Tatiana P. Ugarova
• 刊名：Biochemistry
• 出版年：2015
• 出版时间：February 17, 2015
• 年：2015
• 卷：54
• 期：6
• 页码：1408-1420
• 全文大小：585K
• ISSN：1520-4995

文摘

The broad recognition specificity exhibited by integrin 伪_M尾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 伪_M尾₂ binds its multiple ligands. Within 伪_M尾₂, the 伪_MI-domain is responsible for integrin鈥檚 multiligand binding properties. To identify its recognition motif, we screened peptide libraries spanning sequences of many known protein ligands for 伪_MI-domain binding and also selected the 伪_MI-domain recognition sequences by phage display. Analyses of >1400 binding and nonbinding peptides derived from peptide libraries showed that a key feature of the 伪_MI-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 伪_MI-domain binding sites in the 伪_M尾₂ ligands. The recognition specificity of the 伪_MI-domain resembles that of some chaperones, which allows it to bind segments exposed in unfolded proteins. The disclosure of the 伪_M尾₂ binding preferences allowed the prediction that cationic host defense peptides, which are strikingly enriched in the 伪_MI-domain recognition motifs, represent a new class of 伪_M尾₂ ligands. This prediction has been tested by examining the interaction of 伪_M尾₂ with the human cathelicidin peptide LL-37. LL-37 induced a potent 伪_M尾₂-dependent cell migratory response and caused activation of 伪_M尾₂ on neutrophils. The newly revealed recognition specificity of 伪_M尾₂ toward unfolded protein segments and cationic proteins and peptides suggests that 伪_M尾₂ may serve as a previously proposed 鈥渁larmin鈥?receptor with important roles in innate host defense.