1tb6

Structural highlights

Disease

[THRB_HUMAN] Defects in F2 are the cause of factor II deficiency (FA2D) [MIM:613679]. It is a very rare blood coagulation disorder characterized by mucocutaneous bleeding symptoms. The severity of the bleeding manifestations correlates with blood factor II levels.^{[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12]} Genetic variations in F2 may be a cause of susceptibility to ischemic stroke (ISCHSTR) [MIM:601367]; also known as cerebrovascular accident or cerebral infarction. A stroke is an acute neurologic event leading to death of neural tissue of the brain and resulting in loss of motor, sensory and/or cognitive function. Ischemic strokes, resulting from vascular occlusion, is considered to be a highly complex disease consisting of a group of heterogeneous disorders with multiple genetic and environmental risk factors.^[13] Defects in F2 are the cause of thrombophilia due to thrombin defect (THPH1) [MIM:188050]. It is a multifactorial disorder of hemostasis characterized by abnormal platelet aggregation in response to various agents and recurrent thrombi formation. Note=A common genetic variation in the 3-prime untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increased risk of venous thrombosis. Defects in F2 are associated with susceptibility to pregnancy loss, recurrent, type 2 (RPRGL2) [MIM:614390]. A common complication of pregnancy, resulting in spontaneous abortion before the fetus has reached viability. The term includes all miscarriages from the time of conception until 24 weeks of gestation. Recurrent pregnancy loss is defined as 3 or more consecutive spontaneous abortions.^[14] [ANT3_HUMAN] Defects in SERPINC1 are the cause of antithrombin III deficiency (AT3D) [MIM:613118]. AT3D is an important risk factor for hereditary thrombophilia, a hemostatic disorder characterized by a tendency to recurrent thrombosis. AT3D is classified into 4 types. Type I: characterized by a 50% decrease in antigenic and functional levels. Type II: has defects affecting the thrombin-binding domain. Type III: alteration of the heparin-binding domain. Plasma AT-III antigen levels are normal in type II and III. Type IV: consists of miscellaneous group of unclassifiable mutations.^[15] [:]^{[16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36]} [:]^{[37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49]}

Function

[THRB_HUMAN] Thrombin, which cleaves bonds after Arg and Lys, converts fibrinogen to fibrin and activates factors V, VII, VIII, XIII, and, in complex with thrombomodulin, protein C. Functions in blood homeostasis, inflammation and wound healing.^[50] [ANT3_HUMAN] Most important serine protease inhibitor in plasma that regulates the blood coagulation cascade. AT-III inhibits thrombin, matriptase-3/TMPRSS7, as well as factors IXa, Xa and XIa. Its inhibitory activity is greatly enhanced in the presence of heparin.^[51]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

See Also

• Antithrombin
• Thrombin

References

1. ↑ Wang W, Fu Q, Zhou R, Wu W, Ding Q, Hu Y, Wang X, Wang H, Wang Z. Prothrombin Shanghai: hypoprothrombinaemia caused by substitution of Gla29 by Gly. Haemophilia. 2004 Jan;10(1):94-7. PMID:14962227
2. ↑ Board PG, Shaw DC. Determination of the amino acid substitution in human prothrombin type 3 (157 Glu leads to Lys) and the localization of a third thrombin cleavage site. Br J Haematol. 1983 Jun;54(2):245-54. PMID:6405779
3. ↑ Rabiet MJ, Furie BC, Furie B. Molecular defect of prothrombin Barcelona. Substitution of cysteine for arginine at residue 273. J Biol Chem. 1986 Nov 15;261(32):15045-8. PMID:3771562
4. ↑ Miyata T, Morita T, Inomoto T, Kawauchi S, Shirakami A, Iwanaga S. Prothrombin Tokushima, a replacement of arginine-418 by tryptophan that impairs the fibrinogen clotting activity of derived thrombin Tokushima. Biochemistry. 1987 Feb 24;26(4):1117-22. PMID:3567158
5. ↑ Inomoto T, Shirakami A, Kawauchi S, Shigekiyo T, Saito S, Miyoshi K, Morita T, Iwanaga S. Prothrombin Tokushima: characterization of dysfunctional thrombin derived from a variant of human prothrombin. Blood. 1987 Feb;69(2):565-9. PMID:3801671
6. ↑ Henriksen RA, Mann KG. Identification of the primary structural defect in the dysthrombin thrombin Quick I: substitution of cysteine for arginine-382. Biochemistry. 1988 Dec 27;27(26):9160-5. PMID:3242619
7. ↑ Henriksen RA, Mann KG. Substitution of valine for glycine-558 in the congenital dysthrombin thrombin Quick II alters primary substrate specificity. Biochemistry. 1989 Mar 7;28(5):2078-82. PMID:2719946
8. ↑ Miyata T, Aruga R, Umeyama H, Bezeaud A, Guillin MC, Iwanaga S. Prothrombin Salakta: substitution of glutamic acid-466 by alanine reduces the fibrinogen clotting activity and the esterase activity. Biochemistry. 1992 Aug 25;31(33):7457-62. PMID:1354985
9. ↑ Morishita E, Saito M, Kumabashiri I, Asakura H, Matsuda T, Yamaguchi K. Prothrombin Himi: a compound heterozygote for two dysfunctional prothrombin molecules (Met-337-->Thr and Arg-388-->His). Blood. 1992 Nov 1;80(9):2275-80. PMID:1421398
10. ↑ Iwahana H, Yoshimoto K, Shigekiyo T, Shirakami A, Saito S, Itakura M. Detection of a single base substitution of the gene for prothrombin Tokushima. The application of PCR-SSCP for the genetic and molecular analysis of dysprothrombinemia. Int J Hematol. 1992 Feb;55(1):93-100. PMID:1349838
11. ↑ James HL, Kim DJ, Zheng DQ, Girolami A. Prothrombin Padua I: incomplete activation due to an amino acid substitution at a factor Xa cleavage site. Blood Coagul Fibrinolysis. 1994 Oct;5(5):841-4. PMID:7865694
12. ↑ Degen SJ, McDowell SA, Sparks LM, Scharrer I. Prothrombin Frankfurt: a dysfunctional prothrombin characterized by substitution of Glu-466 by Ala. Thromb Haemost. 1995 Feb;73(2):203-9. PMID:7792730
13. ↑ Casas JP, Hingorani AD, Bautista LE, Sharma P. Meta-analysis of genetic studies in ischemic stroke: thirty-two genes involving approximately 18,000 cases and 58,000 controls. Arch Neurol. 2004 Nov;61(11):1652-61. PMID:15534175 doi:61/11/1652
14. ↑ Pihusch R, Buchholz T, Lohse P, Rubsamen H, Rogenhofer N, Hasbargen U, Hiller E, Thaler CJ. Thrombophilic gene mutations and recurrent spontaneous abortion: prothrombin mutation increases the risk in the first trimester. Am J Reprod Immunol. 2001 Aug;46(2):124-31. PMID:11506076
15. ↑ Lindo VS, Kakkar VV, Learmonth M, Melissari E, Zappacosta F, Panico M, Morris HR. Antithrombin-TRI (Ala382 to Thr) causing severe thromboembolic tendency undergoes the S-to-R transition and is associated with a plasma-inactive high-molecular-weight complex of aggregated antithrombin. Br J Haematol. 1995 Mar;89(3):589-601. PMID:7734359
16. ↑ Bock SC, Marrinan JA, Radziejewska E. Antithrombin III Utah: proline-407 to leucine mutation in a highly conserved region near the inhibitor reactive site. Biochemistry. 1988 Aug 9;27(16):6171-8. PMID:3191114
17. ↑ Lane DA, Bayston T, Olds RJ, Fitches AC, Cooper DN, Millar DS, Jochmans K, Perry DJ, Okajima K, Thein SL, Emmerich J. Antithrombin mutation database: 2nd (1997) update. For the Plasma Coagulation Inhibitors Subcommittee of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Thromb Haemost. 1997 Jan;77(1):197-211. PMID:9031473
18. ↑ Koide T, Odani S, Takahashi K, Ono T, Sakuragawa N. Antithrombin III Toyama: replacement of arginine-47 by cysteine in hereditary abnormal antithrombin III that lacks heparin-binding ability. Proc Natl Acad Sci U S A. 1984 Jan;81(2):289-93. PMID:6582486
19. ↑ Chang JY, Tran TH. Antithrombin III Basel. Identification of a Pro-Leu substitution in a hereditary abnormal antithrombin with impaired heparin cofactor activity. J Biol Chem. 1986 Jan 25;261(3):1174-6. PMID:3080419
20. ↑ Stephens AW, Thalley BS, Hirs CH. Antithrombin-III Denver, a reactive site variant. J Biol Chem. 1987 Jan 25;262(3):1044-8. PMID:3805013
21. ↑ Devraj-Kizuk R, Chui DH, Prochownik EV, Carter CJ, Ofosu FA, Blajchman MA. Antithrombin-III-Hamilton: a gene with a point mutation (guanine to adenine) in codon 382 causing impaired serine protease reactivity. Blood. 1988 Nov;72(5):1518-23. PMID:3179438
22. ↑ Erdjument H, Lane DA, Panico M, Di Marzo V, Morris HR. Single amino acid substitutions in the reactive site of antithrombin leading to thrombosis. Congenital substitution of arginine 393 to cysteine in antithrombin Northwick Park and to histidine in antithrombin Glasgow. J Biol Chem. 1988 Apr 25;263(12):5589-93. PMID:3162733
23. ↑ Erdjument H, Lane DA, Panico M, Di Marzo V, Morris HR, Bauer K, Rosenberg RD. Antithrombin Chicago, amino acid substitution of arginine 393 to histidine. Thromb Res. 1989 Jun 15;54(6):613-9. PMID:2781509
24. ↑ Borg JY, Brennan SO, Carrell RW, George P, Perry DJ, Shaw J. Antithrombin Rouen-IV 24 Arg----Cys. The amino-terminal contribution to heparin binding. FEBS Lett. 1990 Jun 18;266(1-2):163-6. PMID:2365065
25. ↑ Gandrille S, Aiach M, Lane DA, Vidaud D, Molho-Sabatier P, Caso R, de Moerloose P, Fiessinger JN, Clauser E. Important role of arginine 129 in heparin-binding site of antithrombin III. Identification of a novel mutation arginine 129 to glutamine. J Biol Chem. 1990 Nov 5;265(31):18997-9001. PMID:2229057
26. ↑ Austin RC, Rachubinski RA, Blajchman MA. Site-directed mutagenesis of alanine-382 of human antithrombin III. FEBS Lett. 1991 Mar 25;280(2):254-8. PMID:2013320
27. ↑ Perry DJ, Daly M, Harper PL, Tait RC, Price J, Walker ID, Carrell RW. Antithrombin Cambridge II, 384 Ala to Ser. Further evidence of the role of the reactive centre loop in the inhibitory function of the serpins. FEBS Lett. 1991 Jul 22;285(2):248-50. PMID:1906811
28. ↑ Olds RJ, Lane DA, Boisclair M, Sas G, Bock SC, Thein SL. Antithrombin Budapest 3. An antithrombin variant with reduced heparin affinity resulting from the substitution L99F. FEBS Lett. 1992 Apr 6;300(3):241-6. PMID:1555650
29. ↑ Blajchman MA, Fernandez-Rachubinski F, Sheffield WP, Austin RC, Schulman S. Antithrombin-III-Stockholm: a codon 392 (Gly----Asp) mutation with normal heparin binding and impaired serine protease reactivity. Blood. 1992 Mar 15;79(6):1428-34. PMID:1547341
30. ↑ Okajima K, Abe H, Maeda S, Motomura M, Tsujihata M, Nagataki S, Okabe H, Takatsuki K. Antithrombin III Nagasaki (Ser116-Pro): a heterozygous variant with defective heparin binding associated with thrombosis. Blood. 1993 Mar 1;81(5):1300-5. PMID:8443391
31. ↑ Olds RJ, Lane DA, Beresford CH, Abildgaard U, Hughes PM, Thein SL. A recurrent deletion in the antithrombin gene, AT106-108(-6 bp), identified by DNA heteroduplex detection. Genomics. 1993 Apr;16(1):298-9. PMID:8486379 doi:http://dx.doi.org/10.1006/geno.1993.1184
32. ↑ Emmerich J, Vidaud D, Alhenc-Gelas M, Chadeuf G, Gouault-Heilmann M, Aillaud MF, Aiach M. Three novel mutations of antithrombin inducing high-molecular-mass compounds. Arterioscler Thromb. 1994 Dec;14(12):1958-65. PMID:7981186
33. ↑ Millar DS, Wacey AI, Ribando J, Melissari E, Laursen B, Woods P, Kakkar VV, Cooper DN. Three novel missense mutations in the antithrombin III (AT3) gene causing recurrent venous thrombosis. Hum Genet. 1994 Nov;94(5):509-12. PMID:7959685
34. ↑ Jochmans K, Lissens W, Vervoort R, Peeters S, De Waele M, Liebaers I. Antithrombin-Gly 424 Arg: a novel point mutation responsible for type 1 antithrombin deficiency and neonatal thrombosis. Blood. 1994 Jan 1;83(1):146-51. PMID:8274732
35. ↑ van Boven HH, Olds RJ, Thein SL, Reitsma PH, Lane DA, Briet E, Vandenbroucke JP, Rosendaal FR. Hereditary antithrombin deficiency: heterogeneity of the molecular basis and mortality in Dutch families. Blood. 1994 Dec 15;84(12):4209-13. PMID:7994035
36. ↑ Bruce D, Perry DJ, Borg JY, Carrell RW, Wardell MR. Thromboembolic disease due to thermolabile conformational changes of antithrombin Rouen-VI (187 Asn-->Asp) J Clin Invest. 1994 Dec;94(6):2265-74. PMID:7989582 doi:http://dx.doi.org/10.1172/JCI117589
37. ↑ Emmerich J, Chadeuf G, Alhenc-Gelas M, Gouault-Heilman M, Toulon P, Fiessinger JN, Aiach M. Molecular basis of antithrombin type I deficiency: the first large in-frame deletion and two novel mutations in exon 6. Thromb Haemost. 1994 Oct;72(4):534-9. PMID:7878627
38. ↑ Okajima K, Abe H, Wagatsuma M, Okabe H, Takatsuki K. Antithrombin III Kumamoto II; a single mutation at Arg393-His increased the affinity of antithrombin III for heparin. Am J Hematol. 1995 Jan;48(1):12-8. PMID:7832187
39. ↑ Ozawa T, Takikawa Y, Niiya K, Fujiwara T, Suzuki K, Sato S, Sakuragawa N. Antithrombin Morioka (Cys 95-Arg): a novel missense mutation causing type I antithrombin deficiency. Thromb Haemost. 1997 Feb;77(2):403. PMID:9157604
40. ↑ Fitches AC, Appleby R, Lane DA, De Stefano V, Leone G, Olds RJ. Impaired cotranslational processing as a mechanism for type I antithrombin deficiency. Blood. 1998 Dec 15;92(12):4671-6. PMID:9845533
41. ↑ Jochmans K, Lissens W, Seneca S, Capel P, Chatelain B, Meeus P, Osselaer JC, Peerlinck K, Seghers J, Slacmeulder M, Stibbe J, van de Loo J, Vermylen J, Liebaers I, De Waele M. The molecular basis of antithrombin deficiency in Belgian and Dutch families. Thromb Haemost. 1998 Sep;80(3):376-81. PMID:9759613
42. ↑ Picard V, Bura A, Emmerich J, Alhenc-Gelas M, Biron C, Houbouyan-Reveillard LL, Molho P, Labatide-Alanore A, Sie P, Toulon P, Verdy E, Aiach M. Molecular bases of antithrombin deficiency in French families: identification of seven novel mutations in the antithrombin gene. Br J Haematol. 2000 Sep;110(3):731-4. PMID:10997988
43. ↑ Niiya K, Kiguchi T, Dansako H, Fujimura K, Fujimoto T, Iijima K, Tanimoto M, Harada M. Two novel gene mutations in type I antithrombin deficiency. Int J Hematol. 2001 Dec;74(4):469-72. PMID:11794707
44. ↑ Baud O, Picard V, Durand P, Duchemin J, Proulle V, Alhenc-Gelas M, Devictor D, Dreyfus M. Intracerebral hemorrhage associated with a novel antithrombin gene mutation in a neonate. J Pediatr. 2001 Nov;139(5):741-3. PMID:11713457 doi:10.1067/mpd.2001.118191
45. ↑ Mushunje A, Zhou A, Huntington JA, Conard J, Carrell RW. Antithrombin 'DREUX' (Lys 114Glu): a variant with complete loss of heparin affinity. Thromb Haemost. 2002 Sep;88(3):436-43. PMID:12353073 doi:10.1267/THRO88030436
46. ↑ Picard V, Dautzenberg MD, Villoutreix BO, Orliaguet G, Alhenc-Gelas M, Aiach M. Antithrombin Phe229Leu: a new homozygous variant leading to spontaneous antithrombin polymerization in vivo associated with severe childhood thrombosis. Blood. 2003 Aug 1;102(3):919-25. Epub 2003 Feb 20. PMID:12595305 doi:10.1182/blood-2002-11-3391
47. ↑ Nagaizumi K, Inaba H, Amano K, Suzuki M, Arai M, Fukutake K. Five novel and four recurrent point mutations in the antithrombin gene causing venous thrombosis. Int J Hematol. 2003 Jul;78(1):79-83. PMID:12894857
48. ↑ David D, Ribeiro S, Ferrao L, Gago T, Crespo F. Molecular basis of inherited antithrombin deficiency in Portuguese families: identification of genetic alterations and screening for additional thrombotic risk factors. Am J Hematol. 2004 Jun;76(2):163-71. PMID:15164384 doi:10.1002/ajh.20067
49. ↑ Kuhli C, Jochmans K, Scharrer I, Luchtenberg M, Hattenbach LO. Retinal vein occlusion associated with antithrombin deficiency secondary to a novel G9840C missense mutation. Arch Ophthalmol. 2006 Aug;124(8):1165-9. PMID:16908819 doi:10.1001/archopht.124.8.1165
50. ↑ Glenn KC, Frost GH, Bergmann JS, Carney DH. Synthetic peptides bind to high-affinity thrombin receptors and modulate thrombin mitogenesis. Pept Res. 1988 Nov-Dec;1(2):65-73. PMID:2856554
51. ↑ Szabo R, Netzel-Arnett S, Hobson JP, Antalis TM, Bugge TH. Matriptase-3 is a novel phylogenetically preserved membrane-anchored serine protease with broad serpin reactivity. Biochem J. 2005 Aug 15;390(Pt 1):231-42. PMID:15853774 doi:BJ20050299
52. ↑ Li W, Johnson DJ, Esmon CT, Huntington JA. Structure of the antithrombin-thrombin-heparin ternary complex reveals the antithrombotic mechanism of heparin. Nat Struct Mol Biol. 2004 Sep;11(9):857-62. Epub 2004 Aug 15. PMID:15311269 doi:10.1038/nsmb811