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Original Article |
Correspondence to: Erkki Koivunen, Department of Biosciences, Division of Biochemistry, University of Helsinki, Viikinkaari 5, FIN-00014 Helsinki, Finland. Tel:(358) 9-191-59023 Fax:(358) 9-191-59068 E-mail:erkki.koivunen{at}helsinki.fi.
Many integrins mediate cell attachment to the extracellular matrix by recognizing short tripeptide sequences such as arginineglycineaspartic acid and leucineaspartatevaline. Using phage display, we have now found that the leukocyte-specific ß2 integrins bind sequences containing a leucineleucineglycine (LLG) tripeptide motif. An LLG motif is present on intercellular adhesion molecule (ICAM)-1, the major ß2 integrin ligand, but also on several matrix proteins, including von Willebrand factor. We developed a novel ß2 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 ß2 integrinmediated leukocyte adhesion, but not ß1 or ß3 integrinmediated 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.
Key Words: cell adhesion, extracellular matrix, leukocyte, phage display, peptides
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