I-DOMAIN OF BETA(2) INTEGRIN LYMPHOCYTE FUNCTION-ASSOCIATED ANTIGEN-1 CONTAINS A BINDING-SITE FOR LIGAND INTERCELLULAR-ADHESION MOLECULE-1

Lymphocyte function-associated antigen-1 (LFA-1) is a beta(2) integrin that participates in a broad range of leukocyte functions through binding to its ligand intercellular adhesion molecule-1 (ICAM-1). The location of the ICAM-1 binding site on LFA-1 is not known. A similar to 200-amino acid ''inserted'' or ''I'' domain, which is part of the beta(2) integrin alpha subunit, is homologous to the ''A'' domains found in the adhesive protein von Willebrand factor and in a number of other proteins. In von Willebrand factor the A domains are involved in ligand binding, but their function in the other proteins is still unclear. In this report, we show that the LFA-1 I domain contains a binding site for ICAM-1, which can be expressed as an isolated functional unit. The I domain contains the epitopes for 18 out of 20 anti-LFA-1 monoclonal antibodies, many of which interfere with the interaction between LFA-1 and ICAM-1. The I domain binds directly to purified recombinant ICAM-1 and also inhibits LFA-1-dependent T cell adhesion to ICAM-1. This report establishes the I domain as an ICAM-1 binding region in LFA-1 and the first ligand binding site to be identified in a beta(2) integrin.