Identification of a novel recognition sequence for integrin α(M)β2 within the γ-chain of fibrinogen

Tatiana P. Ugarova, Dmitry A. Solovjov, Li Zhang, Dmitry I. Loukinov, Vivien C. Yee, Leonid V. Medved, Edward F. Plow

Research output: Contribution to journalArticle

126 Scopus citations

Abstract

The interaction of leukocyte integrin α(M)β2 (CD11b/CD18, Mac-1) with fibrinogen has been implicated in the inflammatory response by contributing to leukocyte adhesion to the endothelium and subsequent transmigration. Previously, it has been demonstrated that a peptide, P1, corresponding to residues 190-202 in the γ-chain of fibrinogen, binds to α(M)β2 and blocks the interaction of fibrinogen with the receptor and that Asp199 within P1 is important to activity. We have demonstrated, however, that a double mutation of Asp199Gly200 to Gly-Ala in the recombinant γ-module of fibrinogen, spanning region 148-411, did not abrogate α(M)β2 recognition and considered that other binding sites in the γ-module may participate in the receptor recognition. We have found that synthetic peptide P2, duplicating γ377-395, inhibited adhesion of α(M)β2-transfected cells to immobilized D100 fragment of fibrinogen in a dose-dependent manner. In addition, immobilized P2 directly supported efficient adhesion of the α(M)β2-expressing cells, including activated and non-activated monocytoid cells. The I domain of α(M)β2 was implicated in recognition of P2, as the biotinylated recombinant α(M)I domain specifically bound to both P2 and P1 peptides. Analysis of overlapping peptides spanning P2 demonstrated that it may contain two functional sequences: γ377-386 (P2-N) and γ383-395 (P2-C), with the latter sequence being more active. In the three-dimensional structure of the γ-module, γ190-202 and γ377-395 reside in close proximity, forming two antiparallel β strands. The juxtapositioning of these two sequences may form an unique and complex binding site for α(M)β2.

Original languageEnglish (US)
Pages (from-to)22519-22527
Number of pages9
JournalJournal of Biological Chemistry
Volume273
Issue number35
DOIs
StatePublished - Aug 28 1998
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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