Exposure of acidic residues as a danger signal for recognition of fibrinogen and other macromolecules by integrin αxβ2

The structural integrity of tissue proteins is damaged in processes ranging from remodeling of the extracellular matrix to destruction by microbial pathogens. Leukocytes play a prominent role in tissue surveillance and repair. However, it remains enigmatic what features of structurally decayed proteins prompt recognition by leukocyte cell-surface receptors. Here, we report that adhesion of human neutrophil granulocytes to fibrinogen is greatly increased by plasmin digestion in a mode where αXβ2 dominates the integrin-dependent binding. The bacterial protease subtilisin also enhances binding by αXβ2. The αX ligand binding domain has an unusually high affinity for carboxyl groups, with KD at ≈100 μM. Our findings implicate enhanced accessibility of negatively charged residues in structurally decayed proteins as a pattern recognition motif for αXβ2 integrin. Comparisons among integrins show relevance of these findings to the large number of ligands recognized by αMβ2 and αXβ2 but not αLβ2. The observations suggest that the pericellular proteolysis at the leading edge of neutrophils not only facilitates passage through the extracellular matrix but also manufactures binding sites for αXβ2.