Critical amino acids in the lymphocyte function-associated antigen-1 I domain mediate intercellular adhesion molecule 3 binding and immune function.
We have identified amino acid residues within the evolutionarily conserved I domain of the alpha-chain (CD11a) of the leukocyte integrin leukocyte function-associated antigen (LFA) 1 that are critical for intercellular adhesion molecule (ICAM) 3 (CD50) binding. ICAM-3, a ligand of LFA-1, is thought to mediate intercellular adhesion essential for the initiation of immune responses. Using a panel of human/murine I domain chimeras and point mutants, we observed that the Ile-Lys-Gly-Asn motif, located in the NH2-terminal part of the CD11a I domain, is required for ICAM-3 but not ICAM-1 binding. These findings demonstrate that the I domain of CD11a contains distinct functional subdomains for ligand specific binding. An aspartic acid located at position 137, which is essential to ICAM-1/LFA-1 interactions (Edwards, C.P., M. Champe, T. Gonzalez, M.E. Wessinger, S.A. Spencer, L.G. Presta, P.W. Berman, and S.C. Bodary. 1995. J. Biol. Chem. 270:12635-12640), was also critical for ICAM-3 binding, whereas Ser at position 139 did not effect ICAM-1 or ICAM-3 binding. A synthetic peptide containing the Ile-Lys-Gly-Asn motif inhibited ICAM-3-dependent adhesion and proliferation of T cells at micromolar concentrations, suggesting that this peptide interferes with immune recognition. These observations underscore the importance of ICAM-3 in leukocyte function, and may lead to development of a new category of immunosuppressive agents.
van Kooyk
Y
Y
Department of Tumor Immunology, University of Nijmegen, The Netherlands.
Binnerts
M E
ME
Edwards
C P
CP
Champe
M
M
Berman
P W
PW
Figdor
C G
CG
Bodary
S C
SC
D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation; D001665:Binding Sites; D005075:Biological Evolution; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002460:Cell Line; D017124:Conserved Sequence; D015870:Gene Expression; D006801:Humans; D007700:Kinetics; D016169:Lymphocyte Function-Associated Antigen-1 / Q000737:chemistry* / Q000276:immunology / Q000502:physiology*; D051379:Mice; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000494:pharmacology; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D017354:Point Mutation; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D014162:Transfection
D015703:Antigens, CD; D000943:Antigens, Differentiation; D015815:Cell Adhesion Molecules; C483616:ICAM3 protein, human; D016169:Lymphocyte Function-Associated Antigen-1; D010446:Peptide Fragments; D010455:Peptides; D011993:Recombinant Fusion Proteins