The structural motif glycine 190-valine 202 of the fibrinogen gamma chain interacts with CD11b/CD18 integrin (alpha M beta 2, Mac-1) and promotes leukocyte adhesion

• Published in: The Journal of biological chemistry 1993-01, Vol.268 (3), p.1847-1853
• Main Authors: ALTIERI, D. C, PLESCIA, J, PLOW, E. F
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Analytical, structural and metabolic biochemistry; Antibodies, Monoclonal; Antigens, CD - metabolism; Binding and carrier proteins; Biological and medical sciences; CD11 Antigens; CD18 Antigens; Cell Adhesion - physiology; Cell Line; Fibrinogen - chemistry; Fibrinogen - immunology; Fibrinogen - metabolism; Fundamental and applied biological sciences. Psychology; Glycine - chemistry; Humans; Integrins - metabolism; Leukocytes - physiology; Leukocytes, Mononuclear - metabolism; Molecular Sequence Data; N-Formylmethionine Leucyl-Phenylalanine - pharmacology; Neutrophils - metabolism; Peptide Fragments - chemistry; Peptide Fragments - immunology; Peptide Fragments - metabolism; Proteins; Valine - chemistry
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1016/S0021-9258(18)53932-6

The leukocyte-restricted integrin CD11b/CD18 (alpha M beta 2, Mac-1) is a receptor for fibrinogen on stimulated monocytes and neutrophils. At variance with platelet alpha IIb beta 3 or endothelial cell alpha v beta 3 integrins, CD11b/CD18 interacts with a approximately 30-kDa plasmic fragment D (D30) of fibrinogen that lacks the Arg-Gly-Asp sequences in the A alpha chain and the carboxyl terminus of the gamma chain. Using epitope-mapped antibodies and synthetic peptidyl mimicry, we have now identified a unique linear sequence in fibrinogen that mediates ligand binding to CD11b/CD18. Anti-fibrinogen antibodies directed to the gamma chain region 95-264 inhibited 125I-fibrinogen or 125I-D30 binding to chemoattractant-stimulated neutrophils or monocytic THP-1 cells in a dose-dependent fashion. Partially overlapping synthetic peptides reproducing this gamma chain region were tested for their ability to inhibit fibrinogen binding to leukocytes. A synthetic peptide designated P1, duplicating gamma chain Gly190-Val202, inhibited 125I-fibrinogen binding to stimulated neutrophils or THP-1 cells and blocked adhesion of these cells to immobilized fibrinogen in a dose-dependent fashion. Increasing concentrations of P1 inhibited 125I-fibrinogen binding to isolated CD11b/CD18 in a cell-free system. Consistent with genuine peptidyl mimicry, 125I-P1 bound saturably to THP-1 cells in a reaction inhibited by molar excess of unlabeled peptide, fibrinogen, or D30. Finally, immobilized P1 effectively supported adhesion of THP-1 cells in a CD11b/CD18-dependent manner. These data suggest that the fibrinogen gamma chain region Gly190-Val202 functions as a minimal recognition sequence for the leukocyte integrin CD11b/CD18. Given the participation of fibrinogen:leukocyte interaction in inflammation and atherogenesis, antagonists based on this unique structural motif would effectively interfere with aberrant leukocyte adhesion mechanisms without affecting Arg-Gly-Asp-directed vascular integrins.