| 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] [GP1BA_HUMAN] Genetic variations in GP1BA may be a cause of susceptibility to non-arteritic anterior ischemic optic neuropathy (NAION) [MIM:258660]. NAION is an ocular disease due to ischemic injury to the optic nerve. It usually affects the optic disk and leads to visual loss and optic disk swelling of a pallid nature. Visual loss is usually sudden, or over a few days at most and is usually permanent, with some recovery possibly occurring within the first weeks or months. Patients with small disks having smaller or non-existent cups have an anatomical predisposition for non-arteritic anterior ischemic optic neuropathy. As an ischemic episode evolves, the swelling compromises circulation, with a spiral of ischemia resulting in further neuronal damage.[15] Defects in GP1BA are a cause of Bernard-Soulier syndrome (BSS) [MIM:231200]; also known as giant platelet disease (GPD). BSS patients have unusually large platelets and have a clinical bleeding tendency.[16] [17] [18] [19] [20] [21] Defects in GP1BA are the cause of benign mediterranean macrothrombocytopenia (BMM) [MIM:153670]; also known as autosomal dominant benign Bernard-Soulier syndrome. BMM is characterized by mild or no clinical symptoms, normal platelet function, and normal megakaryocyte count.[22] Defects in GP1BA are the cause of pseudo-von Willebrand disease (VWDP) [MIM:177820]. A bleeding disorder is caused by an increased affinity of GP-Ib for soluble vWF resulting in impaired hemostatic function due to the removal of vWF from the circulation.[23] [24] [25] [26]
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.[27] [GP1BA_HUMAN] GP-Ib, a surface membrane protein of platelets, participates in the formation of platelet plugs by binding to the A1 domain of vWF, which is already bound to the subendothelium.
Publication Abstract from PubMed
The involvement of exosite I in alpha-thrombin (FIIa) binding to platelet glycoprotein Ibalpha (GPIbalpha), which could influence interactions with other substrates, remains undefined. To address the problem, we generated the GPIbalpha amino terminal domain (GPIbalpha-N) fully sulfated on three tyrosine residues and solved the structure of its complex with FIIa. We found that sulfotyrosine (Tys) 278 enhances the interaction mainly by establishing contacts with exosite I. We then evaluated how substituting tyrosine with phenylalanine, which cannot be sulfated, affects FIIa binding to soluble or surface-immobilized GPIbalpha-N. Mutating Tyr(276), which mostly contacts exosite II residues, markedly reduced FIIa interaction with both soluble and immobilized GPIbalpha-N; mutating Tyr(278) or Tyr(279), which mostly contact exosite I residues, reduced FIIa complexing in solution by 0-20% but affinity for immobilized GPIbalpha-N 2 to 6-fold, respectively. Moreover, three exosite I ligands-aptamer HD1, hirugen, and lepirudin-did not interfere with soluble FIIa complexing to GPIbalpha-N, excluding that their binding caused allosteric effects influencing the interaction; nonetheless, all impaired FIIa binding to immobilized GPIbalpha-N and platelet GPIb nearly as much as aptamer HD22 and heparin, both exosite II ligands. Bound HD1 and hirugen alter Trp(148) orientation in a loop near exosite I preventing contacts with the sulfate oxygen atoms of Tys(279). These results support a mechanism in which binding occurs when the two exosites of one FIIa molecule independently interact with two immobilized GPIbalpha molecules. Through exosite engagement, GPIbalpha may influence FIIa-dependent processes relevant to hemostasis and thrombosis.
Binding of {alpha}-thrombin to surface-anchored platelet glycoprotein Ib{alpha} sulfotyrosines through a two-site mechanism involving exosite I.,Zarpellon A, Celikel R, Roberts JR, McClintock RA, Mendolicchio GL, Moore KL, Jing H, Varughese KI, Ruggeri ZM Proc Natl Acad Sci U S A. 2011 May 24;108(21):8628-33. Epub 2011 May 9. PMID:21555542[28]
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
- ↑ Salomon O, Rosenberg N, Steinberg DM, Huna-Baron R, Moisseiev J, Dardik R, Goldan O, Kurtz S, Ifrah A, Seligsohn U. Nonarteritic anterior ischemic optic neuropathy is associated with a specific platelet polymorphism located on the glycoprotein Ibalpha gene. Ophthalmology. 2004 Jan;111(1):184-8. PMID:14711733 doi:10.1016/j.ophtha.2003.05.006
- ↑ Miller JL, Lyle VA, Cunningham D. Mutation of leucine-57 to phenylalanine in a platelet glycoprotein Ib alpha leucine tandem repeat occurring in patients with an autosomal dominant variant of Bernard-Soulier disease. Blood. 1992 Jan 15;79(2):439-46. PMID:1730088
- ↑ Ware J, Russell SR, Marchese P, Murata M, Mazzucato M, De Marco L, Ruggeri ZM. Point mutation in a leucine-rich repeat of platelet glycoprotein Ib alpha resulting in the Bernard-Soulier syndrome. J Clin Invest. 1993 Sep;92(3):1213-20. PMID:7690774 doi:http://dx.doi.org/10.1172/JCI116692
- ↑ Simsek S, Noris P, Lozano M, Pico M, von dem Borne AE, Ribera A, Gallardo D. Cys209 Ser mutation in the platelet membrane glycoprotein Ib alpha gene is associated with Bernard-Soulier syndrome. Br J Haematol. 1994 Dec;88(4):839-44. PMID:7819107
- ↑ de la Salle C, Baas MJ, Lanza F, Schwartz A, Hanau D, Chevalier J, Gachet C, Briquel ME, Cazenave JP. A three-base deletion removing a leucine residue in a leucine-rich repeat of platelet glycoprotein Ib alpha associated with a variant of Bernard-Soulier syndrome (Nancy I). Br J Haematol. 1995 Feb;89(2):386-96. PMID:7873390
- ↑ Kenny D, Jonsson OG, Morateck PA, Montgomery RR. Naturally occurring mutations in glycoprotein Ibalpha that result in defective ligand binding and synthesis of a truncated protein. Blood. 1998 Jul 1;92(1):175-83. PMID:9639514
- ↑ Koskela S, Partanen J, Salmi TT, Kekomaki R. Molecular characterization of two mutations in platelet glycoprotein (GP) Ib alpha in two Finnish Bernard-Soulier syndrome families. Eur J Haematol. 1999 Mar;62(3):160-8. PMID:10089893
- ↑ Savoia A, Balduini CL, Savino M, Noris P, Del Vecchio M, Perrotta S, Belletti S, Poggi, Iolascon A. Autosomal dominant macrothrombocytopenia in Italy is most frequently a type of heterozygous Bernard-Soulier syndrome. Blood. 2001 Mar 1;97(5):1330-5. PMID:11222377
- ↑ Matsubara Y, Murata M, Sugita K, Ikeda Y. Identification of a novel point mutation in platelet glycoprotein Ibalpha, Gly to Ser at residue 233, in a Japanese family with platelet-type von Willebrand disease. J Thromb Haemost. 2003 Oct;1(10):2198-205. PMID:14521605
- ↑ Miller JL, Cunningham D, Lyle VA, Finch CN. Mutation in the gene encoding the alpha chain of platelet glycoprotein Ib in platelet-type von Willebrand disease. Proc Natl Acad Sci U S A. 1991 Jun 1;88(11):4761-5. PMID:2052556
- ↑ Murata M, Russell SR, Ruggeri ZM, Ware J. Expression of the phenotypic abnormality of platelet-type von Willebrand disease in a recombinant glycoprotein Ib alpha fragment. J Clin Invest. 1993 May;91(5):2133-7. PMID:8486780 doi:http://dx.doi.org/10.1172/JCI116438
- ↑ Russell SD, Roth GJ. Pseudo-von Willebrand disease: a mutation in the platelet glycoprotein Ib alpha gene associated with a hyperactive surface receptor. Blood. 1993 Apr 1;81(7):1787-91. PMID:8384898
- ↑ 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
- ↑ Zarpellon A, Celikel R, Roberts JR, McClintock RA, Mendolicchio GL, Moore KL, Jing H, Varughese KI, Ruggeri ZM. Binding of {alpha}-thrombin to surface-anchored platelet glycoprotein Ib{alpha} sulfotyrosines through a two-site mechanism involving exosite I. Proc Natl Acad Sci U S A. 2011 May 24;108(21):8628-33. Epub 2011 May 9. PMID:21555542 doi:10.1073/pnas.1017042108
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