A pseudosymmetric cell adhesion regulatory domain in the beta7 tail of the integrin alpha4beta7 that interacts with focal adhesion kinase and src.
The beta7 integrins alpha4beta7 and alphaEbeta7 play key roles in forming the gut-associated lymphoid tissue, and contribute to chronic inflammation. The alpha4beta7 integrin-mediated adhesion of activated lymphocytes is largely due to a transient increase in avidity from ligand-induced clustering of alpha4beta7 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 beta7 subunit inhibit the adhesion of T cells to beta7 integrin ligands. The YDRREY peptide abrogated mucosal addressin cell adhesion molecule-1-induced clustering of alpha4beta7 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 alpha4beta7. The quasi-palindromic sequence YDRREY within the beta7 cytoplasmic tail constitutes a cell adhesion regulatory domain that modulates the interaction of beta7-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.
Krissansen
Geoffrey W
GW
Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand. gw.krissansen@auckland.ac.nz
Singh
Jaison
J
Kanwar
Rupinder K
RK
Chan
Yih-Chih
YC
Leung
Euphemia
E
Lehnert
Klaus B
KB
Kanwar
Jagat R
JR
Yang
Yi
Y
D000595:Amino Acid Sequence; D000818:Animals; D002448:Cell Adhesion; D002460:Cell Line; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism*; D006801:Humans; D016023:Integrins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008024:Ligands; D051379:Mice; D008969:Molecular Sequence Data; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011485:Protein Binding; D021122:Protein Subunits / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism
D016023:Integrins; D008024:Ligands; D021122:Protein Subunits; C071777:integrin alpha4beta7; D019000:Phosphotyrosine; D051416:Focal Adhesion Protein-Tyrosine Kinases; D016392:Proto-Oncogene Proteins pp60(c-src)