Protein Science, Vol 1, Issue 1 151-160, Copyright © 1992 by Cold Spring Harbor Laboratory Press

ARTICLE

The sequence HGLGHGHEQQHGLGHGH in the light chain of high molecular weight kininogen serves as a primary structural feature for zinc-dependent binding to an anionic surface

R. A. DELA-CADENA and R. W. COLMAN
Thrombosis Research Center

The histidine-glycine-rich region of the light chain of cleaved high molecular weight kininogen (HK) is thought to be responsible for binding to negatively charged surfaces and initiation of the intrinsic coagulation, fibrinolytic, and kinin-forming systems. However, the specifically required amino acid sequences have not been delineated. An IgG fraction of a monoclonal antibody (MAb) C11C1 to the HK light chain was shown to inhibit by 66% the coagulant activity and by 57% the binding of HK to the anionic surface of kaolin at a concentration of 1.5 {mu}M and 27 {mu}M, respectively. Proteolytic fragments of HK were produced by successive digestion with human plasma kallikrein and factor XIa (FXIa). Those polypeptides that bound tightly (K(d) = 0.77 nM) to a C11C1 affinity column were eluted at pH 3.0 and purified by membrane filtration. On 15% SDS polyacrylamide electrophoresis, the approximate M(r) was 7.3 kDa (range 6.2-8.1 kDa). Based on N-terminal sequencing, this polypeptide (l(2)), which extends from the histidine residue 459 to a lysine at position 505, 509, 511, 512, 515, or 520, inhibits by 50% the coagulant activity expressed by HK at a concentration of 22 {mu}M. The synthetic peptide HGLGHGH representing the N-terminal of the l(2) fragment was synthesized, tested, and found at 4 mM to inhibit the procoagulant activity of HK 50%. A synthetic heptadecapeptide, HGLGHGHEQQHGLGHGH (residues 459-475) included within the l(2) fragment, and with the ability to bind zinc, inhibited 50% of the HK coagulant activity at a concentration of 325 {mu}M in the absence and presence of added Zn(2+) (30 {mu}M). The specific binding of (125)I-HK to a negatively charged surface (kaolin) was inhibited 50% by unlabeled HK (5 {mu}M). HGLGHGH, at a concentration of 7.0 mM, inhibited the binding to kaolin by 50%. The heptadecapeptide inhibited the specific binding of (125)I-HK to kaolin by 50%, at a concentration of 2.3 mM, in the absence of Zn(2+). In contrast, when Zn(2+) was added, the concentration to achieve 50% inhibition decreased to 630 {mu}M, indicating that Zn(2+) was required to attain a favorable conformation for binding. Moreover, the l(2) fragment was found to inhibit 50% of the (125)I-HK binding to kaolin at a concentration of 380 {mu}M. These results suggest that residues contained within the l(2) fragment, notably NGLGHGHEQQHGLGHGH, serves as a primary structural feature for binding to a negatively charged surface.
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