Identification of a binding site for integrin alphaEbeta7 in the N-terminal domain of E-cadherin.
The integrin alphaEbeta7, which is predominantly expressed on mucosal T lymphocytes, has recently been shown to recognize the cell adhesion molecule, E-cadherin, on epithelial cells. We have carried out mutations on E-cadherin, involving domain deletions as well as substitutions of specific amino acids, in order to identify the sites recognized by the integrin. Binding of alphaEbeta7 required the presence of the first two N-terminal domains of E-cadherin. Deletion of extracellular domains 3 and 4 or truncation of the cytoplasmic domain of E-cadherin had no consequence on integrin binding. Substitution of a glutamic acid in the BC loop of the Ig structure of the fist, N-terminal, domain of E-cadherin abrogated binding of alphaEbeta7. This mutation did not appear to affect the conformation of the domain nor the pattern of expression of E-cadherin on the cell surface. Synthetic peptides encompassing the first domain of E-cadherin had very little inhibitory effect on the interaction with alphaEbeta7. Our results highlight structural dissimilarities between recognition of E-cadherin by alphaEbeta7 and recognition of other members of the IgSF by integrins and show that the heterophilic (integrin binding) and homophilic sites in the N-terminal domain of E-cadherin are distinct.
Karecla
P I
PI
Department of Immunology, The Babraham Institute, Babraham, Cambridge CB2 4AT, United Kingdom.
Green
S J
SJ
Bowden
S J
SJ
Coadwell
J
J
Kilshaw
P J
PJ
D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000737:chemistry*; D001665:Binding Sites; D015820:Cadherins / Q000737:chemistry*; D002448:Cell Adhesion; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000737:chemistry; D051180:Desmoplakins; D004848:Epithelium / Q000502:physiology; D019084:Fluorescent Antibody Technique, Indirect; D039001:Integrin alpha Chains; D039641:Integrin beta Chains; D016023:Integrins / Q000737:chemistry*; D007739:L Cells; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D016415:Sequence Alignment; D017384:Sequence Deletion; D015398:Signal Transduction; D013329:Structure-Activity Relationship
D015703:Antigens, CD; D015820:Cadherins; D003598:Cytoskeletal Proteins; D051180:Desmoplakins; D039001:Integrin alpha Chains; D039641:Integrin beta Chains; D016023:Integrins; C091367:alpha E integrins; C091368:integrin beta7