|
 DOMAIN STRUCTURE OF FACTOR XII The organization of the factor XII domain structure based on sequence homology
is represented, where: EGF=epidermal growth factor, Type I and Type II=domains homologous
to those found in fibronectin, solid arrows=kallikrein cleavage sites that form
a- and β-factor
XIIa, dashed
arrows=cleavages leading to intermediate forms of factor
XIIa.
Factor XII (XII) (Hageman Factor) is a single chain (Mr=78,000) glycoprotein zymogen that circulates in plasma at a concentration of 40 mg/ml (1-5). Reciprical activation of XII to the active serine protease factor XIIa (XIIa) by kallikrein is central to initiation of the intrinsic coagulation pathway. Surface bound
α-XIIa in turn activates
factor XI to XIa. Secondary cleavage of
α-XIIa by kallikrein yields
β-XIIa, which catalyzes solution phase activation of kallikrein,
factor VII and the classical complement cascade.
The ability of a variety of negatively charged substances, both physiological and nonphysiological to promote XII activation and, thus, initiation of the intrinsic pathway has led to the psuedonym "contact activation". Binding to anionic surfaces induces a conformational change, making the XII zymogen more susceptible to cleavage by a variety of proteases (6,7). It is unlikely that binding to negatively charged surfaces alone is sufficient to activate XII, since highly purified preparations of XII and plasma deficient in prekallikrein and high molecular weight kininogen do not undergo this "autocatalysis" (8-11).
A single cleavage by kallikrein at R353-Val354 of XII yields α-XIIa, a 2 chain protease (Mr=80,000) held together by disulfide bonds. The COOH-terminal light chain (Mr=28,000) contains the catalytic triad (His-40, Asp-89, Ser-191), while the
NH2-terminal heavy chain (Mr=52,000) conatins the anionic surface binding portion of the molecule. A secondary cleavage of
α-XIIa by kallikrein outside the disulfide bond yields
β-XIIa (XIIf, BHFa,
HFf, hageman factor fragments) (Mr=28,000), which no longer binds anionic surfaces (12).
β-XIIa can activate prekallikrein, but has little procoagulant activity (13,14). Several other minor intermediate forms of XIIa are indicated in the figure above.
Inhibitors of XIIa include C1-INH, α2-antiplasmin,
α2-macroglobulin and
antithrombin III. At physiological concentrations, the relative effectiveness of these inhibitors is 91 : 4.5 : 3 : 1.5, respectively (10, 16-19). The ratio of C1-INH to XII has been implicated in the "cold activation" of factor VII and the conversion of prorenin to renin on storage of plasma (20,21).
Human factor XII is prepared from fresh frozen plasma by immunoaffinity chromatography and supplied in 50% glycerol for storage at
-20oC.
Properties of Factor
XII
| Localization: |
Plasma |
| Plasma concentration: |
40 µg/ml (3) |
| Mode of action: |
Zymogen; precursor to the serine protease factor
XIIa; activated by kallikrein/HMWK/anionic surface complex to intitiate the intrinsic pathway |
| Molecular weight: |
80,000 (2) |
| Extinction coefficient: |
|
| Isoelectric point: |
6.8 |
| Structure: |
single chain
(mr=80,000), organized into 6 domains based on sequence homology (5). |
| Percent carbohydrate: |
17% |
|
Catalog
Number |
Description |
|
HCXII-0155 |
Human Factor XII |
PRICING
INQUIRE
ABOUT THIS PRODUCT
References
1. Schmaier, A.H., et al., in Hemostasis and Thrombosis, ed. R.W. Colman, J. Hirsh, V.J. Marder and E.W. Salzman, pp 18-38, J.B. Lippincott Company, Philadelphia, 1987.
2. Griffin, J.H. and Cochrane, C.G., Methods Enzymol., 45, 56-65 (1976).
3. Saito, H., et al., J Lab Clin., 88, 506 (1976).
4. McMullen, B.A. and Fujikawa, N., J. Biol. Chem., 260, 5328 (1985).
5. Davie, E.W., in Hemostasis and Thrombosis, ed. R.W. Colman, J. Hirsh, V.J. Marder and E.W. Salzman, pp 242-267, J.B. Lippincott Company, Philadelphia, 1987.
6. Griffin, J.H., Proc. Natl. Acad. Sci. USA, 75, 1998 (1978).
7. McMillin, L.R., et al., J. Clin. Invest., 54, 1312 (1974).
8. Revak, S.D., et al., J. Clin. Invest., 59, 1167 (1977).
9. Fujikawa, K., et al., Biochemistry, 16, 4182 (1977).
10. Bonno, N., et al., in New Comprehensive Biochemistry, ed. R.F.A. Zwaal and H.C.Hemker, pp. 103-128,
Elsevier, Amsterdam, 1986.
11. Claeys, H. and Collen, D. (1978) Eur. J. Biochem., 87, 69 (1978).
12. Revak, S.D. and Cochrane, C.G., J. Clin. Invest., 57, 852 (1976).
13. Cochrane, C.G., et al., J. Exp. Med., 138, 1564 (1973).
14. Revak, S.D., et al., J. Exp. Med., 147, 719 (1978).
15. Ghebrehiwet, B., et al., J. Clin. Invest., 71, 1458 (1983).
16. DeAgostini, A., et al., J. Clin. Invest., 73, 1542 (1984).
17. Rathoff, O.D., et al., J. Exp. Med., 129, 315 (1969).
18. Stead, N., et al., J. Biol Chem., 251, 6481 (1976).
19. Pixley, R.A., et al., J. Biol Chem., 260, 1723 (1985).
20. Gjonnass, H., Thromb. Diath. Haemorrh., 28, 182 (1972).
21. Radcliffe, R., et al., Blood, 59, 611 (1977).
|
