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f12

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Official Full Name
coagulation factor XII (Hageman factor)
Background
Coagulation factor XII also known as Hageman factor is a plasma protein. It is the zymogen form of factor XIIa, an enzyme (EC 3.4.21.38) of the serine protease (or serine endopeptidase) class. In humans, factor XII is encoded by the F12 gene.
Synonyms
coagulation factor XII (Hageman factor); F12; HAF; HAE3; HAEX; coagulation factor XII; Hageman factor; OTTHUMP00000223845; beta-factor XIIa part 1; beta-factor XIIa part 2; coagulation factor XIIa heavy chain; coagulation factor XIIa light chain

Functions & Recent Research Progress

F12 and serine protease

As a serine protease, Coagulation factor XII is important blood coagulation, cleaving the substrates plasma kallikrein and FXI. A series of recombinant F12 protease constructs were characterized by measurement of cleavage of chromogenic peptide and plasma kallikrein protein substrates. This revealed that the F12 protease construct spanning the light chain has unexpectedly weak proteolytic activity compared to β-F12 a, which has an additional nine amino acid remnant of the heavy chain present. The study found that the crystal structure of the light chain protease reveals a zymogen conformation for active site residues Gly193 and Ser195, where the oxyanion hole is absent. The Asp194 side chain salt bridge to Arg73 constitutes an atypical conformation of the 70-loop. In one crystal form, the S1 pocket loops are partially flexible, which is typical of a zymogen. In a second crystal form of the deglycosylated light chain, the S1 pocket loops are ordered, and a short ɑ-helix in the 180‐loop of the structure results in an enlarged and distorted S1 pocket with a buried conformation of Asp189, which is critical for P1 Arg substrate recognition. The F12 structures define patches of negative charge surrounding the active site cleft that may be critical for interactions with inhibitors and substrates.

Figure 1.Prothrombin activation (Nickel Katrin F,2017)

The active form of F12

F12 is a plasma protease that in its active form (F12a) initiates the procoagulant and proinflammatory contact system. This name arises from F12’s unique mechanism of activation that is induced by binding (contact) to negatively charged surfaces. When blood is in contact with negatively charged collagen (the outer wall of the skin's blood vessels) or an allogeneic surface (such as kaolin, glass, etc.), Factor XII is activated by zymogen to XIIa, which activates pre-motorized kallikrein in addition to stimulating factor XI. Activation of kallikrein, under the promotion of high molecular weight kininogen, in turn further activates factor XII, but at this time it is no longer contact activation but peptide bond hydrolysis activation, making it a factor XIIf. This is a positive feedback effect, whether XIIa or XIIf have the same vitality. Various substances have the capacity to trigger F12 contact-activation in vivo including mast cell-derived heparin, misfolded protein aggregates, collagen, nucleic acids, and polyphosphate. However, despite the fact that humans and animals with deficiency in F12 have a normal hemostatic capacity, animal models revealed a critical role of F12a-driven coagulation in thromboembolic diseases. In addition to its role in thrombosis, F12a contributes to inflammation through the activation of the inflammatory bradykinin-producing kallikrein-kinin system. Pharmacological inhibition of F12/F12a interferes with thrombosis and inflammation in animal models. Thus, targeting the F12a-driven contact system seems to be a promising and safe therapeutic anticoagulation treatment strategy, with additional anti-inflammatory effects.

F12 and ogen

Activated coagulation factor XII (ɑ-F12a) is able to bind to fibrin(ogen) and increases the density and stiffness of the fibrin clot. Conversely, proteins of the contact system and the fibrinolytic system show a high degree of homology and ɑ-F12a can convert plasminogen into plasmin resulting in fibrin degradation.

Conclusion

Surface-induced activation of coagulation factor XII is a critical part of the intrinsic pathway of blood coagulation, and its active form (F12a) can initiate procoagulant and proinflammatory contact systems. In addition, activated coagulation factor XII plays an important role in overall clot stability and fibrinolysis. Factor XII is a serine protease that is important for kinin production and blood coagulation, cleavage of substrate plasma kallikrein and FXI.

References:

  1. Joke Konings, et al. The role of activated coagulation factor XII in overall clot stability and fibrinolysis. Thrombosis Research, 2015, 474-480.
  2. M. Pathak, et al. Coagulation factor XII protease domain crystal structure. Journal of Thrombosis and Haemostasis, 2015, 580-591.
  3. Nickel Katrin F, et al. Factor XII as a Therapeutic Target in Thromboembolic and Inflammatory Diseases. Arteriosclerosis, thrombosis, and vascular biology, 2017, 13-20.