Critical amino acids in the lymphocyte function-associated antigen-1 I domain mediate intercellular adhesion molecule 3 binding and immune function

Y van Kooyk, M E Binnerts, C P Edwards, M Champe, P W Berman, C G Figdor, S C Bodary

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)1247-52
Number of pages6
JournalJournal of Experimental Medicine
Volume183
Issue number3
Publication statusPublished - 1 Mar 1996

Cite this

van Kooyk, Y ; Binnerts, M E ; Edwards, C P ; Champe, M ; Berman, P W ; Figdor, C G ; Bodary, S C. / Critical amino acids in the lymphocyte function-associated antigen-1 I domain mediate intercellular adhesion molecule 3 binding and immune function. In: Journal of Experimental Medicine. 1996 ; Vol. 183, No. 3. pp. 1247-52.
@article{34c0c1ac613b43b785b6f3ab195ae53a,
title = "Critical amino acids in the lymphocyte function-associated antigen-1 I domain mediate intercellular adhesion molecule 3 binding and immune function",
abstract = "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.",
keywords = "Amino Acid Sequence, Animals, Antigens, CD, Antigens, Differentiation, Binding Sites, Biological Evolution, Cell Adhesion/drug effects, Cell Adhesion Molecules/metabolism, Cell Line, Conserved Sequence, Gene Expression, Humans, Kinetics, Lymphocyte Function-Associated Antigen-1/chemistry, Mice, Molecular Sequence Data, Mutagenesis, Site-Directed, Peptide Fragments/chemical synthesis, Peptides/chemistry, Point Mutation, Recombinant Fusion Proteins/chemistry, Sequence Homology, Amino Acid, Transfection",
author = "{van Kooyk}, Y and Binnerts, {M E} and Edwards, {C P} and M Champe and Berman, {P W} and Figdor, {C G} and Bodary, {S C}",
year = "1996",
month = "3",
day = "1",
language = "English",
volume = "183",
pages = "1247--52",
journal = "Journal of Experimental Medicine",
issn = "0022-1007",
publisher = "Rockefeller University Press",
number = "3",

}

Critical amino acids in the lymphocyte function-associated antigen-1 I domain mediate intercellular adhesion molecule 3 binding and immune function. / van Kooyk, Y; Binnerts, M E; Edwards, C P; Champe, M; Berman, P W; Figdor, C G; Bodary, S C.

In: Journal of Experimental Medicine, Vol. 183, No. 3, 01.03.1996, p. 1247-52.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Critical amino acids in the lymphocyte function-associated antigen-1 I domain mediate intercellular adhesion molecule 3 binding and immune function

AU - van Kooyk, Y

AU - Binnerts, M E

AU - Edwards, C P

AU - Champe, M

AU - Berman, P W

AU - Figdor, C G

AU - Bodary, S C

PY - 1996/3/1

Y1 - 1996/3/1

N2 - 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.

AB - 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.

KW - Amino Acid Sequence

KW - Animals

KW - Antigens, CD

KW - Antigens, Differentiation

KW - Binding Sites

KW - Biological Evolution

KW - Cell Adhesion/drug effects

KW - Cell Adhesion Molecules/metabolism

KW - Cell Line

KW - Conserved Sequence

KW - Gene Expression

KW - Humans

KW - Kinetics

KW - Lymphocyte Function-Associated Antigen-1/chemistry

KW - Mice

KW - Molecular Sequence Data

KW - Mutagenesis, Site-Directed

KW - Peptide Fragments/chemical synthesis

KW - Peptides/chemistry

KW - Point Mutation

KW - Recombinant Fusion Proteins/chemistry

KW - Sequence Homology, Amino Acid

KW - Transfection

M3 - Article

VL - 183

SP - 1247

EP - 1252

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

SN - 0022-1007

IS - 3

ER -