| 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]
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.[15] [HIRV1_HIRME] Hirudin is a potent thrombin-specific protease inhibitor. It forms a stable non-covalent complex with alpha-thrombin, thereby abolishing its ability to cleave fibrinogen.[16]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
When Na+ binds to thrombin, a conformational change is induced that renders the enzyme kinetically faster and more specific in the activation of fibrinogen. Two Na+ binding sites have here been identified crystallographically by exchanging Na+ with Rb+. One is intermolecular, found on the surface between two symmetry-related thrombin molecules. Since it is not present in thrombin crystal structures having different crystal systems, the other Na+ site is the functionally relevant one. The second site has octahedral coordination with the carbonyl oxygen atoms of Arg221A and Lys224 and four conserved water molecules. It is located near Asp189 of the S1 specificity site in an elongated solvent channel (8 x 18 A) formed by four antiparallel beta-strands between Cys182-Cys191 and Val213-Tyr228. This channel, extending from the active site to the opposite surface of the enzyme, was first noted in the hirudin-thrombin structure and contains about 20 conserved water molecules linked together by a hydrogen bonding network that connects to the main chain of thrombin. Although the antiparallel beta-strand interactions of the functional Na+ binding site are the same in prethrombin2, the loops between the strands are very different, so that Asp189 and Arg221A are not positioned properly for either substrate or Na+ binding in prethrombin2. A water molecule with octahedral coordination has also been identified in factor Xa at the topologically equivalent Na+ site position of thrombin. Since activated protein C shows enhanced activity with monovalant cation binding, the same position is probably utilized by Na+. Since thrombin crystals could not be grown in the absence of Na+, the cation was leached from Na(+)-bound thrombin crystals by diffusion/exchange. Although both Na+ and their coordinating water molecules were removed from the Na+ binding sites, the remainder of the thrombin structure was, unexpectedly, the same. The lack of an allosteric change is most likely attributable to crystal packing effects. Thus, the structure of the slow form remains to be established crystallographically.
The molecular environment of the Na+ binding site of thrombin.,Zhang E, Tulinsky A Biophys Chem. 1997 Jan 31;63(2-3):185-200. PMID:9108691[17]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ Song X, Mo W, Liu X, Zhu L, Yan X, Song H, Dai L. The NMR solution structure of recombinant RGD-hirudin. Biochem Biophys Res Commun. 2007 Aug 17;360(1):103-8. Epub 2007 Jun 13. PMID:17585879 doi:10.1016/j.bbrc.2007.06.014
- ↑ Zhang E, Tulinsky A. The molecular environment of the Na+ binding site of thrombin. Biophys Chem. 1997 Jan 31;63(2-3):185-200. PMID:9108691
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