RGD-containing peptides inhibit fibrinogen binding to platelet alpha(IIb)beta 3 by inducing an allosteric change in the amino-terminal portion of alpha(IIb)
Rb. Basani et al., RGD-containing peptides inhibit fibrinogen binding to platelet alpha(IIb)beta 3 by inducing an allosteric change in the amino-terminal portion of alpha(IIb), J BIOL CHEM, 276(17), 2001, pp. 13975-13981
To determine the molecular basis for the insensitivity of rat alpha (IIb)be
ta (3) to inhibition by RGD-containing peptides, hybrids of human and rat a
lpha (IIb)beta (3) and chimeras of alpha (IIb)beta (3) in which alpha (IIb)
, was composed of portions of human and rat alpha (IIb) were expressed in C
hinese hamster ovary cells and B lymphocytes, and the ability of the tetrap
eptide RGDS to inhibit fibrinogen binding to the various forms of alpha (II
b)beta (3) was measured. These measurements indicated that sequences regula
ting the sensitivity of alpha (IIb)beta (3) to RGDS are located in the seve
n amino-terminal repeats of alpha (IIb). Moreover, replacing the first thre
e or four (but not the first two) repeats of rat alpha (IIb) With the corre
sponding human sequences enhanced sensitivity to RGDS, whereas replacing th
e first two or three repeats of human alpha (IIb) with the corresponding ra
t sequences had little or no effect. Nevertheless, RGDS bound to Chinese ha
mster ovary cells expressing alpha (IIb)beta (3) regardless whether the alp
ha (IIb) in the heterodimers was human, rat, or a rat-human chimera, These
results indicate that the sequences determining the sensitivity of alpha (I
Ib)beta (3) to RGD-containing peptides are located in the third and fourth
amino-terminal repeats of alpha (IIb). Because RGDS binds to both human and
rat alpha (IIb)beta (3), the results suggest that differences in RGDS sens
itivity result from differences in the allosteric changes induced in these
repeats following RGDS binding.