A pseudosymmetric cell adhesion regulatory in the β7 tail of the integrin α4β7 that interacts adhesion kinase and src

The beta 7 integrins alpha 4 beta 7 and alpha E beta 7 play key roles in forming the gut-associated lymphoid tissue, and contribute to chronic inflammation. The alpha 4 beta 7 integrin-mediated adhesion of activated lymphocytes is largely due to a transient increase in avidity from ligand-induced clustering of alpha 4 beta 7 at the cell-surface. Here, we report that L and D enantiomers of a cell-permeable peptide YDRREY encompassing residues 735-740 of the cytoplasmic tail of the beta 7 subunit inhibit the adhesion of T cells to beta 7 integrin ligands. The YDRREY peptide abrogated mucosal addressin cell adhesion molecule-1-induced clustering of alpha 4 beta 7 on the surface of activated T cells. A mutated form of the YDRREY peptide carrying either single or double conservative mutations at Tyr(735)Phe and Tyr(740)Phe was unable to inhibit T cell adhesion, suggesting that both tandem tyrosines are critical for activity. The YDRREY peptide was bound and phosphorylated by focal adhesion kinase and src, which may serve to sequester cytoskeletal proteins to the cytoplasmic domain of alpha 4 beta 7. The quasi-palindromic sequence YDRREY within the beta 7 cytoplasmic tail constitutes a cell adhesion regulatory domain that modulates the interaction of beta 7-expressing leukocytes with their endothelial and epithelial ligands. Cell-permeable peptidomimetics based on this motif have utility as anti-inflammatory reagents for the treatment of chronic inflammatory disease.