Regulated unmasking of the cryptic binding site for integrin αMβ2 in the γC-domain of fibrinogen

Valeryi K. Lishko, Bohdan Kudryk, Valentin P. Yakubenko, Vivien C. Yee, Tatiana P. Ugarova

Research output: Contribution to journalArticle

79 Scopus citations

Abstract

Fibrinogen is a ligand for leukocyte integrin αMβ2 (CD11b/CD18, Mac-1) and mediates adhesion and migration of leukocytes during the immune-inflammatory responses. The binding site for αMβ2 resides in γC, a constituent subdomain in the D-domain of fibrinogen. The sequence γ383-395 (P2-C) in γC was implicated as the major binding site for αMβ2. It is unknown why αMβ2 on leukocytes can bind to immobilized fibrinogen in the presence of high concentrations of soluble fibrinogen in plasma. In this study, we have investigated the accessibility of the binding site in fibrinogen for αMβ2. We found that the αMβ2-binding site in γC is cryptic and identified the mechanism that regulates its unmasking. Proteolytic removal of the small COOH-terminal segment(s) of γC, γ397/405-411, converted the D100 fragment of fibrinogen, which contains intact γC and is not able to inhibit adhesion of the αMβ2-expressing cells, into the fragment D98, which effectively inhibited cell adhesion. D98, but not D100, bound to the recombinant αMI-domain, and the αMI-domain recognition peptide, αM(Glu253-Arg261). Exposure of the P2-C sequence in fibrinogen, D100, and D98 was probed with a site-specific mAb. P2-C is not accessible in soluble fibrinogen and D100 but becomes exposed in D98. P2-C is also unmasked by immobilization of fibrinogen onto a plastic and by deposition of fibrinogen in the extracellular matrix. Thus, exposure of P2-C by immobilization and by proteolysis correlates with unmasking of the αMβ2-binding site in the D-domain. These results demonstrate that conformational alterations regulate the αMβ2-binding site in γC and suggest that processes relevant to tissue injury and inflammation are likely to be involved in the activation of the αMβ2-binding site in fibrinogen.

Original languageEnglish (US)
Pages (from-to)12942-12951
Number of pages10
JournalBiochemistry
Volume41
Issue number43
DOIs
StatePublished - Oct 29 2002

ASJC Scopus subject areas

  • Biochemistry

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