title: Molecular basis for leukocyte integrin alpha(E)beta(7) adhesion to epithelial (E)-cadherin.
abstract: Cadherins are expressed in tissue-restricted patterns and typically mediate homophilic adhesion. Cadherins also mediate lymphocyte adhesion, providing the opportunity for lymphocyte attachment to parenchymal cells. The best characterized example of lymphocyte adhesion to a tissue-specific cell adhesion molecule, as opposed to a vascular endothelial adhesion molecule, is the interaction between integrin alpha(E)beta(7) on intraepithelial lymphocytes and E-cadherin on epithelial cells. However, the molecular basis for an integrin-cadherin interaction is not well defined. Realization that the cadherin domain adopts a topology similar to the immunoglobulin (Ig) fold suggested that integrin recognition of E-cadherin might be similar to recognition of Ig superfamily ligands. Thus, we modeled domain 1 of human E-cadherin and studied the role of solvent-exposed loops that connect Ig-like core-forming beta strands. Mutational analyses localized the integrin alpha(E)beta(7) recognition site to the top of domain 1 at the face formed by the BC and FG loops, a site distinct from the region recognized in intercellular adhesion molecule (ICAM)-1, -2, and -3, mucosal addressin cell adhesion molecule 1 (MAdCAM-1), vascular cell adhesion molecule 1 (VCAM-1), and fibronectin by their integrin ligands. Moreover, the integrin alpha(E)beta(7) binding site is distinct from the homophilic binding site on E-cadherin. These studies provide a conceptual basis for integrin-cadherin binding and extend the model that an Ig-like fold can serve as a scaffold for recognition.
authors.affiliation: Lymphocyte Biology Section, Division of Rheumatology, Immunology and Allergy, Department of Internal Medicine, Bringham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: K S
authors.initials: KS
authors.lastname: Taraszka
authors.forename: J M
authors.initials: JM
authors.lastname: Higgins
authors.forename: K
authors.initials: K
authors.lastname: Tan
authors.forename: D A
authors.initials: DA
authors.lastname: Mandelbrot
authors.forename: J H
authors.initials: JH
authors.lastname: Wang
authors.forename: M B
authors.initials: MB
authors.lastname: Brenner
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites / Q000235:genetics; D001940:Breast / Q000166:cytology / Q000502:physiology; D015820:Cadherins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000737:chemistry; D004847:Epithelial Cells / Q000502:physiology*; D005260:Female; D005353:Fibronectins / Q000737:chemistry; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics / Q000378:metabolism; D016023:Integrins / Q000378:metabolism*; D007962:Leukocytes / Q000502:physiology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding / Q000235:genetics; D020539:Sequence Analysis, Protein; D013601:T-Lymphocytes / Q000502:physiology
chemical_list: D015820:Cadherins; D015815:Cell Adhesion Molecules; D005353:Fibronectins; D007136:Immunoglobulins; D016023:Integrins; C070709:integrin alphaEbeta7