The Surface‐Dependent Autoactivation Mechanism of Factor XII

Abstract

The dependency of concentrations of Zn2+ and the negatively charged surfaces, phosphatidylinositol phosphate (PtdInsP), sulfatide and dextran sulfate, on the autoactivation of human factor XII, has been studied. While the autoactivation induced by sulfatide, and low concentrations of dextran sulfate, was unaffected by the presence of Zn2+, that induced by PtdInsP and higher concentrations of dextran sulfate was completely dependent on Zn2+ : the excess of Zn2+ needed to induce maximal activity with PtdInsP was 12-fold the concentration of factor XII, while with dextran sulfate it was 40-fold. Determination of the Znz+-binding properties of factor XI1 revealed that a total of four zinc ions could bind to each factor XI1 molecule. The first bound zinc ions (Kd 0.1 pM) induced an increase in the intrinsic tryptophan fluorescence of factor XII, while further titration up to a 40-fold surplus resulted in a quenching of the fluorescence. Binding of the zinc ions that caused the quenching had an average Kd of approximately 1 pM, independent of whether it was determined from the fluorescence changes or by equilibrium filtration. Low concentrations of both sulfatide and PtdInsP induced a fluorescence increase similar to that at low concentrations of Zn2+ but, in contrast to sulfatide, higher concentrations of PtdInsP did not induce a quenching in fluorescence. As the Zn2+-independent activating surface (sulfatide) induced quenching in the fluorescence intensity, while the Zn*+-dependent activating surface (PtdInsP) did not, the quenching, whether it was caused by sulfatide or zinc ions, was assigned to a change in the conformation which resulted in a molecular structure of factor XI1 that could be autoactivated. Association of factor XI1 in this conformation on the activating surface was suggested to be responsible for the autoactivation.Keywords: human factor XI1 ; zinc ; autoactivation; negatively charged surfaces ; conformational changes.Factor XI1 (FXII) circulates in normal plasma at a concentration of 30 pg/ml and constitutes, together with prekallikrein and high-molecular-mass kininogen the plasma contact activation system (for reviews see [I-41). It is a monomeric zymogen (80 kDa) that, by a single proteolytic cleavage of the Arg373-Val374 peptide bond within a disulfide loop, is transformed into the serine protease a-factor XIIa (FXIIa). In addition to its function in the contact activation system, it plays a role in the activation of the classical complement pathway as well as in the fibrinolytic system, in the production of kinins and in the initiation of cell-mediated inflammatory responses. By limited proteolysis, FXIIa activates prekallikrein and factor XI1 (autoactivation) and is connected to the intrinsic pathway of coagulation by activation of factor XI. Kallikrein can, in turn, reciprocally activate FXII. In the absence of a procoagulant surface, however, the kallikrein-dependent activation of FXII is slow and FXII autoactivation is practically not detectable [ 5 ] . Negatively charged surfaces stimulat...

Mathematical modeling of material-induced blood plasma coagulation

“…The model predicts that FXII activation and its contribution to blood coagulation is very limited in the absence of procoagulant surface (self-amplification is negligible). Such a result is also consistent with literature demonstrating that foreign surfaces are the key activators of FXII and initiators of the intrinsic pathway [37][38][39][40][41][42][43][44].…”

Histidine-rich glycoprotein binds factor XIIa with high affinity and inhibits contact-initiated coagulation

“…Although it has not been demonstrated, it is possible that dissociation of FXIIa from HRG restores its proteolytic activity, raising the possibility that under certain conditions, FXIIa inhibition may be reversible. This could occur in response to a change in the local pH or Zn 2ϩ concentration, 37 or possibly through alternate ligand binding to HRG. Despite the potential for further complexity, our data suggest that HRG modulates FXIIa-mediated initiation of the contact pathway, thereby limiting systemic FXIIa activation and localizing the procoagulant response.…”

A Mosquito Salivary Protein Inhibits Activation of the Plasma Contact System by Binding to Factor XII and High Molecular Weight Kininogen

“…It is known that Zn 2ϩ ions are necessary for binding of factor XII and HK to the activating surface (3)(4)(5)(6), and it has been reported that Zn 2ϩ binding to these contact factors induces conformational changes in them (7-9). Therefore, it is possible that hamadarin may bind to the receptor-binding domains of these factors by recognizing their conformational change induced by Zn 2ϩ ions.…”

“…k a2 and k d2 represent forward and backward rate constants for the transition from AB to (AB)*, respectively. (3)(4)(5)(6). It has been reported that conformational change is induced within factor XII and HK by Zn 2ϩ binding (7)(8)(9).…”

“…1 Activation of the plasma contact system is initiated by binding of both factor XII and a prekallikrein-HK complex to a biological activating surface such as the endothelial cell surface and then is rapidly amplified by reciprocal activation of kallikrein and factor XII on this surface. Factor XII and HK binding to these surfaces requires Zn 2ϩ ions (3)(4)(5)(6), and Zn 2ϩ ions are thought to induce conformational change in both proteins (7)(8)(9). Activation of the plasma contact system results in the release of a primary mediator of inflammatory reactions, bradykinin, from HK by the generated kallikrein (10).…”