STRUCTURAL RECOGNITION OF A NOVEL FIBRINOGEN GAMMA-CHAIN SEQUENCE(117-133) BY INTERCELLULAR-ADHESION MOLECULE-1 MEDIATES LEUKOCYTE-ENDOTHELIUM INTERACTION
Dc. Altieri et al., STRUCTURAL RECOGNITION OF A NOVEL FIBRINOGEN GAMMA-CHAIN SEQUENCE(117-133) BY INTERCELLULAR-ADHESION MOLECULE-1 MEDIATES LEUKOCYTE-ENDOTHELIUM INTERACTION, The Journal of biological chemistry, 270(2), 1995, pp. 696-699
In addition to its role in hemostasis, fibrinogen is obligatorily requ
ired to mount competent inflammatory responses in vivo. A molecular pr
erequisite of fibrinogen-dependent inflammation may reside in its abil
ity to associate with intercellular adhesion molecule-1 (ICAM-1), and
enhance monocyte adhesion to endothelium by bridging the two cell type
s. Structure-function characterization of the novel ICAM-1 recognition
of fibrinogen was carried out by synthetic peptidyl mimicry of the fi
brinogen gamma chain, A novel peptide sequence, N(117)NQKIVNLKEKVAQLEA
(133), designated gamma 3, dose-dependently inhibited (IC50 similar to
20-40 mu g/ml) binding of I-125 fibrinogen to endothelial cells or IC
AM-1-expressing B lymphoblastoid Daudi cells. In contrast, none of the
previously identified vascular cell fibrinogen interacting sequences
was effective. Increasing concentrations of gamma 3 completely inhibit
ed fibrinogen-mediated adhesion of peripheral blood mononuclear cells
or vitamin D-3-differentiated monocytic HL-60 cells to endothelium, bu
t did not affect leukocyte-endothelium interaction in the absence of f
ibrinogen, I-125-Labeled gamma 3 bound specifically and saturably to g
enetically engineered ICAM-1 transfectants, but not to control non-tra
nsfected cells, and associated with ICAM-1 on cytokine-activated endot
helium with a K-d of 34 mu M. Consistent with functional recognition o
f ICAM-1, immobilized gamma 3 supported adhesion of JY lymphoblasts in
a dose-dependent reaction inhibited by monoclonal antibodies to ICAM-
1. We conclude that a novel fibrinogen gamma 3 sequence N(117)NQKIVNLK
EKVAQLEA(133) binds to ICAM-1 and modulates ICAM-1-dependent adhesion.
These findings define the structural basis of fibrinogen:ICAM-1 recog
nition and provide a potential selective target for inhibiting fibrino
gen-dependent inflammatory responses.