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High molecular weight kininogen binds to platelets by its heavy and light
chains and when bound has altered susceptibility to kallikrein cleavage
FJ Meloni, EJ Gustafson and AH Schmaier
Thrombosis Research Center, Temple University School of Medicine,
Philadelphia, PA.
The unstimulated platelet surface contains a specific and saturable binding
site for high molecular weight kininogen (HK) and low molecular weight
kininogen (LK). Investigations were performed with purified heavy and light
chains of HK to determine which portion(s) of the HK molecule binds to the
platelet surface. Purified 64-Kd heavy chain of HK and 56-Kd light chain of
HK, independently, inhibited 125I-HK binding to unstimulated platelets with
a 50% inhibitory concentration (IC50) of 84 nmol/L (apparent Ki, 30 nmol/L)
and 30 nmol/L (apparent Ki, 11 nM), respectively. The ability of each of
the purified chains of HK to independently inhibit 125I-HK binding was not
due to cleavage, reduction, and alkylation of the protein, because
two-chain HK, produced by treating HK the same way as purifying the
separate chains, inhibited binding similarly to intact HK. Further,
purified LK alone inhibited 125I-HK binding to platelets (Ki, 17 +/- 1
nmol/L, n = 7). The 64-Kd heavy chain of HK was a competitive inhibitor on
a reciprocal plot of 125I-HK-platelet binding with an apparent Ki of 28 +/-
6 nmol/L (n = 4). Independently, purified 56-Kd light chain of HK was also
found to be a competitive inhibitor of 125I-HK-platelet binding, with an
apparent Ki of 11 +/- 3 nmol/L (mean +/- SEM, n = 4). These indirect
studies indicated that HK binds to platelets by two portions of the
molecule, one on the heavy chain and another on the light chain. Studies
with 125I-light chain of HK showed that it specifically bound directly to
platelets in the presence of zinc, since it was blocked by HK, light chain
of HK, or EDTA, but not by LK, C1s, C1 inhibitor, plasmin, factor XIII, or
fibrinogen. Purified light chain of HK did not inhibit direct 125I-LK
binding to platelets. HK was found to bind to platelets in an unmodified
form. HK bound to platelets was cleaved by plasma or urinary kallikrein at
a slower rate than the same concentration of soluble HK or HK bound and
subsequently eluted from the platelet surface. Cleavage of platelet-bound
HK correlated with bradykinin liberation. These studies indicate that HK
has two domains on its molecule that bind to platelets. Further,
platelet-bound HK is protected from kallikreins' proteolysis. This latter
finding suggests that cell binding may modify the rate of bradykinin
liberation from HK.
Volume 79,
Issue 5,
pp. 1233-1244,
03/01/1992
Copyright © 1992 by The American Society of Hematology
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