Inhibition of beta(2) integrin-mediated leukocyte cell adhesion by leucine-leucine-glycine motif-containing peptides.
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.
Koivunen
E
E
Department of Biosciences, Division of Biochemistry, University of Helsinki, Viikinkaari 5, FIN-00014 Helsinki, Finland. erkki.koivunen@helsinki,fi
Ranta
T M
TM
Annila
A
A
Taube
S
S
Uppala
A
A
Jokinen
M
M
van Willigen
G
G
Ihanus
E
E
Gahmberg
C G
CG
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D018821:CD18 Antigens / Q000378:metabolism*; D002413:Cations, Divalent / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D004220:Disulfides / Q000378:metabolism; D004492:Edetic Acid / Q000494:pharmacology; D005976:Glutaral / Q000378:metabolism; D005998:Glycine / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000737:chemistry / Q000378:metabolism; D007930:Leucine / Q000378:metabolism; D007962:Leukocytes / Q000166:cytology* / Q000187:drug effects*; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D019151:Peptide Library; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D011487:Protein Conformation; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013379:Substrate Specificity; D014407:Tumor Cells, Cultured; D014841:von Willebrand Factor / Q000737:chemistry / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D018821:CD18 Antigens; D002413:Cations, Divalent; D004220:Disulfides; D019151:Peptide Library; D010455:Peptides; D011993:Recombinant Fusion Proteins; D014841:von Willebrand Factor; D018799:Intercellular Adhesion Molecule-1; D004492:Edetic Acid; D007930:Leucine; D005976:Glutaral; D005998:Glycine