The leukocyte function-associated antigen-1 (LFA-1)-binding site on ICAM-3 comprises residues on both faces of the first immunoglobulin domain.
ICAM-3 (CD50), a member of the Ig superfamily, is a major ligand for the leukocyte integrin LFA-1 (CD11a/CD18). This interaction represents one of several Ig superfamily/integrin ligand-receptor pairs that have been described to date. ICAM-3 is highly expressed on resting leukocytes and on APCs. In addition to an adhesive function, ICAM-3 can act as a signal-transducing molecule on T cells, providing a costimulatory signal for cell proliferation. Eighteen point mutations in ICAM-3 were generated, and residues important for binding of functional blocking Abs were identified. Mutation of seven of the residues reduced or abrogated adhesion to LFA-1, including three residues that are located on strand A of the ABED face of domain 1. In contrast, extensive mutagenesis analysis of ICAM-1 has shown that only residues on the GFC face interact with LFA-1. Our results provide evidence for a more extensive binding interface between ICAM-3 and LFA-1 than has previously been described. ICAM-3 appears to be unique among the ICAMs in utilizing residues on both faces of domain 1 for interaction with its ligand LFA-1.
ICRF Cell Adhesion Laboratory, University of Oxford, Institute of Molecular Medicine, John Radcliffe Hospital, UK.
E D
ED
Bell
A P
AP
May
D L
DL
Simmons
D000595:Amino Acid Sequence; D019138:Antibodies, Blocking / Q000378:metabolism; D015703:Antigens, CD; D000943:Antigens, Differentiation; D001666:Binding Sites, Antibody / Q000235:genetics; D015815:Cell Adhesion Molecules / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D000939:Epitopes / Q000378:metabolism; D006801:Humans; D007136:Immunoglobulins / Q000737:chemistry / Q000378:metabolism*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed / Q000276:immunology; D017354:Point Mutation / Q000276:immunology; D017434:Protein Structure, Tertiary
D019138:Antibodies, Blocking; D015703:Antigens, CD; D000943:Antigens, Differentiation; D015815:Cell Adhesion Molecules; D000939:Epitopes; C483616:ICAM3 protein, human; D007136:Immunoglobulins; D016169:Lymphocyte Function-Associated Antigen-1