Abstract
Many integrins mediate cell attachment to the extracellular matrix by recognizing short tripeptide sequences such as arginine-glycine-aspartic acid and leucine-aspartate-valine. Using phage display, we have now found that the leukocyte-specific beta(2) integrins bind sequences containing a leucine-leucine-glycine (LLG) tripeptide motif. An LLG motif is present on intercellular adhesion molecule (ICAM)-1, the major beta(2) integrin ligand, but also on several matrix proteins, including von Willebrand factor. We developed a novel beta(2) integrin antagonist peptide CPCFLLGCC (called LLG-C4), the structure of which was determined by nuclear magnetic resonance. The LLG-C4 peptide inhibited leukocyte adhesion to ICAM-1, and, interestingly, also to von Willebrand factor. When immobilized on plastic, the LLG-C4 sequence supported the beta(2) integrin-mediated leukocyte adhesion, but not beta(1) or beta(3) integrin-mediated cell adhesion. These results suggest that LLG sequences exposed on ICAM-1 and on von Willebrand factor at sites of vascular injury play a role in the binding of leukocytes, and LLG-C4 and peptidomimetics derived from it could provide a therapeutic approach to inflammatory reactions.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Motifs
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Amino Acid Sequence
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Anti-Inflammatory Agents / chemical synthesis
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Anti-Inflammatory Agents / chemistry
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Anti-Inflammatory Agents / metabolism
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Anti-Inflammatory Agents / pharmacology*
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CD18 Antigens / metabolism*
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Cations, Divalent / metabolism
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Cell Adhesion / drug effects
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Cell Movement / drug effects*
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Disulfides / metabolism
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Edetic Acid / pharmacology
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Glutaral / metabolism
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Glycine / metabolism
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Humans
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Intercellular Adhesion Molecule-1 / chemistry
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Intercellular Adhesion Molecule-1 / metabolism
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Leucine / metabolism
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Leukocytes / cytology*
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Leukocytes / drug effects*
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Models, Molecular
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Nuclear Magnetic Resonance, Biomolecular
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Peptide Library
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Peptides / chemical synthesis
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Peptides / chemistry
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Peptides / metabolism
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Peptides / pharmacology*
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Protein Binding
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Protein Conformation
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Recombinant Fusion Proteins / metabolism
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Substrate Specificity
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Tumor Cells, Cultured
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von Willebrand Factor / chemistry
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von Willebrand Factor / metabolism
Substances
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Anti-Inflammatory Agents
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CD18 Antigens
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Cations, Divalent
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Disulfides
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Peptide Library
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Peptides
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Recombinant Fusion Proteins
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von Willebrand Factor
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Intercellular Adhesion Molecule-1
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Edetic Acid
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Leucine
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Glutaral
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Glycine