The role of alpha and beta chains in ligand recognition by beta 7 integrins.
Integrins alpha(E)beta(7) and alpha(4)beta(7) are involved in localization of leukocytes at mucosal sites. Although both alpha(E)beta(7) and alpha(4)beta(7) utilize the beta(7) chain, they have distinct binding specificities for E-cadherin and mucosal addressin cell adhesion molecule-1 (MAdCAM-1), respectively. We found that mutation of the metal ion-dependent adhesion site (MIDAS) in the alpha(E) A-domain (D190A) abolished E-cadherin binding, as did mutation F298A on the A-domain surface near the MIDAS cleft. A docking model of the A-domain with E-cadherin domain 1 indicates that coordination of the alpha(E) MIDAS metal ion by E-cadherin Glu(31) and a novel projection of Phe(298) into a hydrophobic pocket on E-cadherin provide the basis for the interaction. The location of the binding site on the alpha(E) A-domain resembles that on other integrins, but its structure appears distinctive and particularly adapted to recognize the tip of E-cadherin, a unique integrin ligand. Additionally, mutation of the beta(7) MIDAS motif (D140A) abolished alpha(E)beta(7) binding to E-cadherin and alpha(4)beta(7)-mediated adhesion to MAdCAM-1, and alpha(4) chain mutations that abrogated binding of alpha(4)beta(1) to vascular cell adhesion molecule-1 and fibronectin similarly reduced alpha(4)beta(7) interaction with MAdCAM-1. Thus, although specificity can be determined by the integrin alpha or beta chain, common structural features of both subunits are required for recognition of dissimilar ligands.
Higgins
J M
JM
Lymphocyte Biology Section, Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. jhiggins@rics.bwh.harvard.edu
Cernadas
M
M
Tan
K
K
Irie
A
A
Wang
J
J
Takada
Y
Y
Brenner
M B
MB
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D016466:CHO Cells; D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules; D006224:Cricetinae; D004591:Electrophoresis, Polyacrylamide Gel; D018604:Epitope Mapping; D005353:Fibronectins / Q000378:metabolism; D005434:Flow Cytometry; D018698:Glutamic Acid / Q000737:chemistry; D006801:Humans; D007136:Immunoglobulins / Q000378:metabolism; D039641:Integrin beta Chains; D016023:Integrins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D020014:K562 Cells; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009088:Mucoproteins / Q000378:metabolism; D009154:Mutation; D010649:Phenylalanine / Q000737:chemistry; D011233:Precipitin Tests; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D014162:Transfection; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D000911:Antibodies, Monoclonal; D015820:Cadherins; D015815:Cell Adhesion Molecules; D005353:Fibronectins; D007136:Immunoglobulins; D039641:Integrin beta Chains; D016023:Integrins; D008024:Ligands; C504265:MADCAM1 protein, human; D009088:Mucoproteins; D019010:Vascular Cell Adhesion Molecule-1; C091368:integrin beta7; D018698:Glutamic Acid; D010649:Phenylalanine