Fibrinogen Binds to Integrin  5 1via the Carboxyl-Terminal RGD Site of the A -Chain

Abstract

Fibrinogen interactions with vascular endothelial cells are implicated in various physiological and pathophysiological events, including angiogenesis and wound healing. We have shown previously that integrin alpha(5)beta(1) is a fibrinogen receptor on endothelial cells [Suehiro, K., Gailit, J., and Plow, E.F. (1997) J. Biol. Chem. 272, 5360-5366]. In the present study, we have characterized fibrinogen interactions with purified alpha(5)beta(1) and have identified the recognition sequence in fibrinogen for alpha(5)beta(1). The binding of fibrinogen to immobilized alpha(5)beta(1) was selectively supported by Mn(2+). Fibrinogen bound to purified alpha(5)beta(1) in a time-dependent, specific, and saturable manner in the presence of Mn(2+), and the binding was blocked completely by Arg-Gly-Asp (RGD)-containing peptides and by anti-alpha(5) and anti-alpha(5)beta(1) monoclonal antibodies. A monoclonal antibody directed to the C-terminal RGD sequence at Aalpha572-574 significantly inhibited the binding of fibrinogen to alpha(5)beta(1), whereas monoclonal antibodies directed to either the N-terminal RGD sequence at Aalpha95-97 or the C-terminus of the gamma-chain did not. Furthermore, substituting RGE for RGD at position Aalpha95-97 in recombinant fibrinogen had a minimal effect on binding, whereas substituting RGE for RGD at position Aalpha572-574 decreased binding by 90%. These results demonstrate that the C-terminal RGD sequence at Aalpha572-574 is required for the interaction of fibrinogen with alpha(5)beta(1).

Fibrinogen Is a Ligand for the Staphylococcus aureus Microbial Surface Components Recognizing Adhesive Matrix Molecules (MSCRAMM) Bone Sialoprotein-binding Protein (Bbp)

“…Reports have suggested a role for the second A␣ RGD site in binding to the integrins ␣ 5 ␤ 1 and ␣ V ␤ 3 (28). Although further studies are required to determine what downstream effects Bbp binding could have on Fg biology, one possible effect could be a modulation of the Fg A␣-integrin interaction.…”

Transglutaminase-mediated oligomerization of the fibrin(ogen) αC domains promotes integrin-dependent cell adhesion and signaling

“…In particular, the ␤N domains of the central E region interact with VE-cadherin, 38 the ␥ chain sequences located in the coiled coil and ␥C domains of the D regions interact with ICAM-1 and ␣V␤3 integrin, respectively, 39,40 and the ␣C domains interact with ␣V␤3 and ␣5␤1. 5,7,23,41 In this study, we have examined the mechanism of the ␣C domain-mediated interaction of fibrinogen and fibrin with endothelial cells. Notably, in fibrinogen the ␣C domains are monomeric/dimeric, while in fibrin they form ordered cross-linked polymers 24 in which their RGD-containing and other binding sites are brought into close proximity.…”

“…5 Another endothelial cell integrin, ␣5␤1, was also found to interact with fibrin (ogen) in an RGD-dependent manner via this motif. 7,23 According to the current view, in fibrinogen the ␣C domains interact intramolecularly with each other and with the central E region while in fibrin they switch to intermolecular interactions to form ␣ polymers, 24 which are covalently cross-linked by activated plasma transglutaminase factor XIIIa (FXIIIa). 25 Tissue transglutaminase (tTG) also cross-links the ␣C domains in fibrin, although the cross-linking pattern seems to be different.…”

Fibrinogen Stabilizes Placental-Maternal Attachment During Embryonic Development in the Mouse

“…This process may involve the interaction of stromal FN, itself bound to collagen at the surface of decidual cells at the implantation site, 38 with its integrin receptors, eg, ␣ 5 ␤ 1 , on invading spongiotrophoblast cells. 39 Stromal Fg, supplied by the vasculature of the mother, may also bind to FN and/or the ␣ 5 ␤ 1 integrin, 40 stabilizing the fibrinoid layer. FXIII, which is supplied by maternal plasma and by macrophage-derived mononuclear cells in the decidua, is capable of further stabilizing the fibrinoid layer via crosslinking of FN to Fg 41,42 and of FN to decidua-derived collagen.…”