Abstract
The hemostatic response to vascular injury entails a sequence of proteolytic events where several inactive zymogens of the trypsin family are converted to active proteases. The cascade starts with exposure of tissue factor from the damaged endothelium and culminates with conversion of prothrombin to thrombin in a reaction catalyzed by the prothrombinase complex composed of the enzyme factor Xa, cofactor Va, Ca2+, and phospholipids. This cofactor-dependent activation is paradigmatic of analogous reactions of the blood coagulation and complement cascades, which makes elucidation of its molecular mechanism of broad significance to the large class of trypsin-like zymogens to which prothrombin belongs. Because of its relevance as the most important reaction in the physiological response to vascular injury, as well as the main trigger of pathological thrombotic complications, the mechanism of prothrombin activation has been studied extensively. However, a molecular interpretation of this mechanism has become available only recently from important developments in structural biology. Here we review current knowledge on the prothrombin-prothrombinase interaction and outline future directions for the study of this key reaction of the coagulation cascade.
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References
Adams TE, Hockin MF, Mann KG, Everse SJ (2004) The crystal structure of activated protein C-inactivated bovine factor Va: implications for cofactor function. Proc Natl Acad Sci U S A 101(24):8918–8923. https://doi.org/10.1073/pnas.0403072101
Alvadia C, Lim NK, Clerico Mosina V, Oostergetel GT, Dutzler R, Paulino C (2019) Cryo-EM structures and functional characterization of the murine lipid scramblase TMEM16F. Elife 8. https://doi.org/10.7554/eLife.44365
Anderson JR, Li J, Springer TA, Brown A (2022) Structures of VWF tubules before and after concatemerization reveal a mechanism of disulfide bond exchange. Blood 140(12):1419–1430. https://doi.org/10.1182/blood.2022016467
Banner DW, D’Arcy A, Chene C, Winkler FK, Guha A, Konigsberg WH, Nemerson Y, Kirchhofer D (1996) The crystal structure of the complex of blood coagulation factor VIIa with soluble tissue factor. Nature 380(6569):41–46. https://doi.org/10.1038/380041a0
Barranco-Medina S, Murphy M, Pelc L, Chen Z, Di Cera E, Pozzi N (2017) Rational design of protein C activators. Sci Rep 7:44596. https://doi.org/10.1038/srep44596
Beck DO, Bukys MA, Singh LS, Szabo KA, Kalafatis M (2004) The contribution of amino acid region ASP695-TYR698 of factor V to procofactor activation and factor Va function. J Biol Chem 279(4):3084–3095. https://doi.org/10.1074/jbc.M306850200
Bertina RM, Koeleman BP, Koster T, Rosendaal FR, Dirven RJ, de Ronde H, van der Velden PA, Reitsma PH (1994) Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 369(6475):64–67
Bianchini EP, Orcutt SJ, Panizzi P, Bock PE, Krishnaswamy S (2005) Ratcheting of the substrate from the zymogen to proteinase conformations directs the sequential cleavage of prothrombin by prothrombinase. Proc Natl Acad Sci U S A 102(29):10099–10104
Bock PE, Panizzi P, Verhamme IM (2007) Exosites in the substrate specificity of blood coagulation reactions. J Thromb Haemost 5(Suppl 1):81–94
Bode W, Turk D, Karshikov A (1992) The refined 1.9-A X-ray crystal structure of D-Phe-Pro-Arg chloromethylketone-inhibited human alpha-thrombin: structure analysis, overall structure, electrostatic properties, detailed active-site geometry, and structure-function relationships. Protein Sci 1(4):426–471
Bonomi M, Vendruscolo M (2018) Determination of protein structural ensembles using cryo-electron microscopy. Curr Opin Struct Biol 56:37–45. https://doi.org/10.1016/j.sbi.2018.10.006
Bos MH, Camire RM (2012) A bipartite autoinhibitory region within the B-domain suppresses function in factor V. J Biol Chem 287(31):26342–26351. https://doi.org/10.1074/jbc.M112.377168
Boskovic DS, Giles AR, Nesheim ME (1990) Studies of the role of factor Va in the factor Xa-catalyzed activation of prothrombin, fragment 1.2-prethrombin-2, and dansyl-L-glutamyl-glycyl-L-arginine-meizothrombin in the absence of phospholipid. J Biol Chem 265(18):10497–10505
Brandstetter H, Bauer M, Huber R, Lollar P, Bode W (1995) X-ray structure of clotting factor IXa: active site and module structure related to Xase activity and hemophilia B. Proc Natl Acad Sci U S A 92(21):9796–9800. https://doi.org/10.1073/pnas.92.21.9796
Brandstetter H, Kuhne A, Bode W, Huber R, von der Saal W, Wirthensohn K, Engh RA (1996) X-ray structure of active site-inhibited clotting factor Xa. Implications for drug design and substrate recognition. J Biol Chem 271(47):29988–29992
Broze GJ Jr, Girard TJ (2013) Factor V, tissue factor pathway inhibitor, and east Texas bleeding disorder. J Clin Invest 123(9):3710–3712. https://doi.org/10.1172/JCI71220
Brufatto N, Nesheim ME (2003) Analysis of the kinetics of prothrombin activation and evidence that two equilibrating forms of prothrombinase are involved in the process. J Biol Chem 278(9):6755–6764. https://doi.org/10.1074/jbc.M206413200
Brufatto N, Ward A, Nesheim ME (2003) Factor Xa is highly protected from antithrombin-fondaparinux and antithrombin-enoxaparin when incorporated into the prothrombinase complex. J Thromb Haemost 1(6):1258–1263. https://doi.org/10.1046/j.1538-7836.2003.00254.x
Bukys MA, Kim PY, Nesheim ME, Kalafatis M (2006) A control switch for prothrombinase: characterization of a hirudin-like pentapeptide from the COOH terminus of factor Va heavy chain that regulates the rate and pathway for prothrombin activation. J Biol Chem 281(51):39194–39204. https://doi.org/10.1074/jbc.M604482200
Camire RM (2011) A new look at blood coagulation factor V. Curr Opin Hematol 18(5):338–342. https://doi.org/10.1097/MOH.0b013e3283497ebc
Camire RM (2021) Blood coagulation factor X: molecular biology, inherited disease, and engineered therapeutics. J Thromb Thrombolysis 52(2):383–390. https://doi.org/10.1007/s11239-021-02456-w
Camire RM, Bos MH (2009) The molecular basis of factor V and VIII procofactor activation. J Thromb Haemost 7(12):1951–1961. https://doi.org/10.1111/j.1538-7836.2009.03622.x
Cheng Y (2018) Single-particle cryo-EM-How did it get here and where will it go. Science 361(6405):876–880. https://doi.org/10.1126/science.aat4346
Childers KC, Peters SC, Spiegel PC Jr (2022) Structural insights into blood coagulation factor VIII: procoagulant complexes, membrane binding, and antibody inhibition. J Thromb Haemost 20(9):1957–1970. https://doi.org/10.1111/jth.15793
Chinnaraj M, Chen Z, Pelc LA, Grese Z, Bystranowska D, Di Cera E, Pozzi N (2018) Structure of prothrombin in the closed form reveals new details on the mechanism of activation. Sci Rep 8(1):2945. https://doi.org/10.1038/s41598-018-21304-1
Dahlback B (2023) Natural anticoagulant discovery, the gift that keeps on giving: finding FV-Short. J Thromb Haemost 21(4):716–727. https://doi.org/10.1016/j.jtha.2023.01.033
Dahlbäck B (2016) Pro- and anticoagulant properties of factor V in pathogenesis of thrombosis and bleeding disorders. Int J Lab Hematol 38(Suppl 1):4–11. https://doi.org/10.1111/ijlh.12508
Davie EW, Fujikawa K, Kisiel W (1991) The coagulation cascade: initiation, maintenance, and regulation. Biochemistry 30(43):10363–10370
Degen SJ, Davie EW (1987) Nucleotide sequence of the gene for human prothrombin. Biochemistry 26(19):6165–6177
Di Cera E (2008) Thrombin. Mol Aspects Med 29(4):203–254
Di Cera E (2020) Mechanisms of ligand binding. Biophys Rev 1(1):011303. https://doi.org/10.1063/5.0020997
Di Cera E, Mohammed BM, Pelc LA, Stojanovski BM (2022) Cryo-EM structures of coagulation factors. Res Pract Thromb Haemost 6(7):e12830. https://doi.org/10.1002/rth2.12830
Esmon CT (2003) The protein C pathway. Chest 124(3 Suppl):26S–32S
Esmon CT, Owen WG, Jackson CM (1974) The conversion of prothrombin to thrombin. V. The activation of prothrombin by factor Xa in the presence of phospholipid. J Biol Chem 249(24):7798–7807
Feng S, Dang S, Han TW, Ye W, ** P, Cheng T, Li J, Jan YN, Jan LY, Cheng Y (2019) Cryo-EM studies of TMEM16F calcium-activated ion channel suggest features important for lipid scrambling. Cell Rep 28(2):567–579 e564. https://doi.org/10.1016/j.celrep.2019.06.023
Frank J (2018) Single-particle reconstruction of biological molecules-story in a sample (Nobel Lecture). Angew Chem Int Ed Engl 57(34):10826–10841. https://doi.org/10.1002/anie.201802770
Fuentes-Prior P, Iwanaga Y, Huber R, Pagila R, Rumennik G, Seto M, Morser J, Light DR, Bode W (2000) Structural basis for the anticoagulant activity of the thrombin-thrombomodulin complex. Nature 404(6777):518–525
Fuglestad B, Gasper PM, Tonelli M, McCammon JA, Markwick PR, Komives EA (2012) The dynamic structure of thrombin in solution. Biophys J 103(1):79–88. https://doi.org/10.1016/j.bpj.2012.05.047. S0006-3495(12)00627-3 [pii]
Fuller JR, Knockenhauer KE, Leksa NC, Peters RT, Batchelor J (2021) Molecular determinants of the factor VIII/von Willebrand factor complex revealed by BIVV001 cryo-electron microscopy. Blood 137(21):2970–2980. https://doi.org/10.1182/blood.2020009197
Gailani D, Broze GJ Jr (1991) Factor XI activation in a revised model of blood coagulation. Science 253(5022):909–912
Gish JS, Jarvis L, Childers KC, Peters SC, Garrels CS, Smith I, Spencer HT, Doering CB, Lollar P, Spiegel PC (2021) Structure of blood coagulation factor VIII in complex with an anti-C1 domain pathogenic antibody inhibitor. Blood 137(21):2981–2986. https://doi.org/10.1182/blood.2020008940
Haynes LM, Bouchard BA, Tracy PB, Mann KG (2012) Prothrombin activation by platelet-associated prothrombinase proceeds through the prethrombin-2 pathway via a concerted mechanism. J Biol Chem 287(46):38647–38655. https://doi.org/10.1074/jbc.M112.407791. M112.407791 [pii]
Hopfner KP, Lang A, Karcher A, Sichler K, Kopetzki E, Brandstetter H, Huber R, Bode W, Engh RA (1999) Coagulation factor IXa: the relaxed conformation of Tyr99 blocks substrate binding. Structure 7(8):989–996. https://doi.org/10.1016/s0969-2126(99)80125-7
Huber R, Bode W (1978) Structural basis of the activation and action of trypsin. Acc Chem Res 11:114–122
Husten EJ, Esmon CT, Johnson AE (1987) The active site of blood coagulation factor Xa. Its distance from the phospholipid surface and its conformational sensitivity to components of the prothrombinase complex. J Biol Chem 262(27):12953–12961
Irons EE, Flatt JW, Doronin K, Fox TL, Acchione M, Stewart PL, Shayakhmetov DM (2013) Coagulation factor binding orientation and dimerization may influence infectivity of adenovirus-coagulation factor complexes. J Virol 87(17):9610–9619. https://doi.org/10.1128/JVI.01070-13
Javitt G, Khmelnitsky L, Albert L, Bigman LS, Elad N, Morgenstern D, Ilani T, Levy Y, Diskin R, Fass D (2020) Assembly mechanism of mucin and von Willebrand factor polymers. Cell 183(3):717–729 e716. https://doi.org/10.1016/j.cell.2020.09.021
Jenny RJ, Pittman DD, Toole JJ, Kriz RW, Aldape RA, Hewick RM, Kaufman RJ, Mann KG (1987) Complete cDNA and derived amino acid sequence of human factor V. Proc Natl Acad Sci U S A 84(14):4846–4850. https://doi.org/10.1073/pnas.84.14.4846
Kalafatis M (2005) Coagulation factor V: a plethora of anticoagulant molecules. Curr Opin Hematol 12(2):141–148. https://doi.org/10.1097/01.moh.0000155016.30296.90
Kalafatis M, Beck DO, Mann KG (2003) Structural requirements for expression of factor Va activity. J Biol Chem 278(35):33550–33561. https://doi.org/10.1074/jbc.M303153200
Kalafatis M, Rand MD, Mann KG (1994) The mechanism of inactivation of human factor V and human factor Va by activated protein C. J Biol Chem 269(50):31869–31880
Kamata K, Kawamoto H, Honma T, Iwama T, Kim SH (1998) Structural basis for chemical inhibition of human blood coagulation factor Xa. Proc Natl Acad Sci U S A 95(12):6630–6635. https://doi.org/10.1073/pnas.95.12.6630
Kim PY, Nesheim ME (2007) Further evidence for two functional forms of prothrombinase each specific for either of the two prothrombin activation cleavages. J Biol Chem 282(45):32568–32581
Krishnaswamy S (2005) Exosite-driven substrate specificity and function in coagulation. J Thromb Haemost 3(1):54–67
Krishnaswamy S (2013) The transition of prothrombin to thrombin. J Thromb Haemost 11(Suppl 1):265–276. https://doi.org/10.1111/jth.12217
Krishnaswamy S, Mann KG, Nesheim ME (1986) The prothrombinase-catalyzed activation of prothrombin proceeds through the intermediate meizothrombin in an ordered, sequential reaction. J Biol Chem 261(19):8977–8984
Lechtenberg BC, Johnson DJ, Freund SM, Huntington JA (2010) NMR resonance assignments of thrombin reveal the conformational and dynamic effects of ligation. Proc Natl Acad Sci U S A 107:14087–14092. https://doi.org/10.1073/pnas.1005255107. 1005255107 [pii]
Lechtenberg BC, Murray-Rust TA, Johnson DJ, Adams TE, Krishnaswamy S, Camire RM, Huntington JA (2013) Crystal structure of the prothrombinase complex from the venom of Pseudonaja textilis. Blood 122(16):2777–2783. https://doi.org/10.1182/blood-2013-06-511733
Lee CJ, Wu S, Eun C, Pedersen LG (2010) A revisit to the one form kinetic model of prothrombinase. Biophys Chem 149(1–2):28–33. https://doi.org/10.1016/j.bpc.2010.03.011. S0301-4622(10)00070-0 [pii]
Lee CJ, Wu S, Pedersen LG (2011) A proposed ternary complex model of prothrombinase with prothrombin: protein-protein docking and molecular dynamics simulations. J Thromb Haemost 9(10):2123–2126. https://doi.org/10.1111/j.1538-7836.2011.04463.x
Mann KG (2003) Thrombin formation. Chest 124(3 Suppl):4S–10S
Mann KG, Butenas S, Brummel K (2003) The dynamics of thrombin formation. Arterioscler Thromb Vasc Biol 23(1):17–25
Mann KG, Kalafatis M (2003) Factor V: a combination of Dr Jekyll and Mr Hyde. Blood 101(1):20–30. https://doi.org/10.1182/blood-2002-01-0290
Mann KG, Nesheim ME, Church WR, Haley P, Krishnaswamy S (1990) Surface-dependent reactions of the vitamin K-dependent enzyme complexes. Blood 76(1):1–16
Martin PD, Malkowski MG, Box J, Esmon CT, Edwards BF (1997) New insights into the regulation of the blood clotting cascade derived from the X-ray crystal structure of bovine meizothrombin des F1 in complex with PPACK. Structure 5(12):1681–1693
Mast AE, Ruf W (2022) Regulation of coagulation by tissue factor pathway inhibitor: implications for hemophilia therapy. J Thromb Haemost 20(6):1290–1300. https://doi.org/10.1111/jth.15697
Mohammed BM, Pelc LA, Rau MJ, Di Cera E (2023) Cryo-EM structure of coagulation factor V short. Blood 141(26):3215–3225. https://doi.org/10.1182/blood.2022019486
Norstrom EA, Tran S, Steen M, Dahlback B (2006) Effects of factor Xa and protein S on the individual activated protein C-mediated cleavages of coagulation factor Va. J Biol Chem 281(42):31486–31494. https://doi.org/10.1074/jbc.M606441200
Orcutt SJ, Krishnaswamy S (2004) Binding of substrate in two conformations to human prothrombinase drives consecutive cleavage at two sites in prothrombin. J Biol Chem 279:54927–54936
Padmanabhan K, Padmanabhan KP, Tulinsky A, Park CH, Bode W, Huber R, Blankenship DT, Cardin AD, Kisiel W (1993) Structure of human des(1-45) factor Xa at 2.2 A resolution. J Mol Biol 232(3):947–966
Papaconstantinou ME, Gandhi PS, Chen Z, Bah A, Di Cera E (2008) Na(+) binding to meizothrombin desF1. Cell Mol Life Sci 65(22):3688–3697
Papagrigoriou E, McEwan PA, Walsh PN, Emsley J (2006) Crystal structure of the factor XI zymogen reveals a pathway for transactivation. Nat Struct Mol Biol 13(6):557–558
Pelc LA, Chen Z, Gohara DW, Vogt AD, Pozzi N, Di Cera E (2015) Why Ser and not Thr brokers catalysis in the trypsin fold. Biochemistry 54:1457–1464. https://doi.org/10.1021/acs.biochem.5b00014
Pineda AO, Carrell CJ, Bush LA, Prasad S, Caccia S, Chen ZW, Mathews FS, Di Cera E (2004) Molecular dissection of Na+ binding to thrombin. J Biol Chem 279(30):31842–31853
Pozzi N, Bystranowska D, Zuo X, Di Cera E (2016a) Structural architecture of prothrombin in solution revealed by single molecule spectroscopy. J Biol Chem 291(35):18107–18116. https://doi.org/10.1074/jbc.M116.738310
Pozzi N, Chen Z, Di Cera E (2016b) How the linker connecting the two kringles influences activation and conformational plasticity of prothrombin. J Biol Chem 291:6071–6082. https://doi.org/10.1074/jbc.M115.700401
Pozzi N, Chen Z, Gohara DW, Niu W, Heyduk T, Di Cera E (2013) Crystal structure of prothrombin reveals conformational flexibility and mechanism of activation. J Biol Chem 288(31):22734–22744. https://doi.org/10.1074/jbc.M113.466946. M113.466946 [pii]
Pozzi N, Chen Z, Pelc LA, Shropshire DB, Di Cera E (2014) The linker connecting the two kringles plays a key role in prothrombin activation. Proc Natl Acad Sci U S A 111(21):7630–7635. https://doi.org/10.1073/pnas.1403779111
Rosing J, Tans G (1997) Factor V. Int J Biochem Cell Biol 29(10):1123–1126. https://doi.org/10.1016/s1357-2725(97)00040-x
Rosing J, Tans G, Govers-Riemslag JW, Zwaal RF, Hemker HC (1980) The role of phospholipids and factor Va in the prothrombinase complex. J Biol Chem 255(1):274–283
Rosing J, Zwaal RF, Tans G (1986) Formation of meizothrombin as intermediate in factor Xa-catalyzed prothrombin activation. J Biol Chem 261(9):4224–4228
Ruben EA, Gandhi PS, Chen Z, Koester SK, DeKoster GT, Frieden C, Di Cera E (2020) (19)F NMR reveals the conformational properties of free thrombin and its zymogen precursor prethrombin-2. J Biol Chem 295(24):8227–8235. https://doi.org/10.1074/jbc.RA120.013419
Ruben EA, Rau MJ, Fitzpatrick J, Di Cera E (2021) Cryo-EM structures of human coagulation factors V and Va. Blood 137(22):3137–3144. https://doi.org/10.1182/blood.2021010684
Ruben EA, Summers B, Rau MJ, Fitzpatrick J, Di Cera E (2022) Cryo-EM structure of the prothrombin-prothrombinase complex. Blood 139(24):3463–3473. https://doi.org/10.1182/blood.2022015807
Schreuder M, Reitsma PH, Bos MHA (2019) Blood coagulation factor Va’s key interactive residues and regions for prothrombinase assembly and prothrombin binding. J Thromb Haemost 17(8):1229–1239. https://doi.org/10.1111/jth.14487
Shen BW, Spiegel PC, Chang CH, Huh JW, Lee JS, Kim J, Kim YH, Stoddard BL (2008) The tertiary structure and domain organization of coagulation factor VIII. Blood 111(3):1240–1247. https://doi.org/10.1182/blood-2007-08-109918
Shi Y, Li C, O’Connor SP, Zhang J, Shi M, Bisaha SN, Wang Y, Sitkoff D, Pudzianowski AT, Huang C, Klei HE, Kish K, Yanchunas J Jr, Liu EC, Hartl KS, Seiler SM, Steinbacher TE, Schumacher WA, Atwal KS, Stein PD (2009) Aroylguanidine-based factor Xa inhibitors: the discovery of BMS-344577. Bioorg Med Chem Lett 19(24):6882–6889. https://doi.org/10.1016/j.bmcl.2009.10.084
Shim JY, Lee CJ, Wu S, Pedersen LG (2015) A model for the unique role of factor Va A2 domain extension in the human ternary thrombin-generating complex. Biophys Chem 199:46–50. https://doi.org/10.1016/j.bpc.2015.02.003
Stojanovski BM, Di Cera E (2021) Role of sequence and position of the cleavage sites in prothrombin activation. J Biol Chem 297(2):100955. https://doi.org/10.1016/j.jbc.2021.100955
Stojanovski BM, Di Cera E (2022) Comparative sequence analysis of vitamin K-dependent coagulation factors. J Thromb Haemost 20(12):2837–2849. https://doi.org/10.1111/jth.15897
Tans G, Janssen-Claessen T, Hemker HC, Zwaal RF, Rosing J (1991) Meizothrombin formation during factor Xa-catalyzed prothrombin activation. Formation in a purified system and in plasma. J Biol Chem 266(32):21864–21873
Toso R, Camire RM (2004) Removal of B-domain sequences from factor V rather than specific proteolysis underlies the mechanism by which cofactor function is realized. J Biol Chem 279(20):21643–21650. https://doi.org/10.1074/jbc.M402107200
Vincent LM, Tran S, Livaja R, Bensend TA, Milewicz DM, Dahlback B (2013) Coagulation factor V(A2440G) causes east Texas bleeding disorder via TFPIalpha. J Clin Invest 123(9):3777–3787. https://doi.org/10.1172/JCI69091
Vu TK, Hung DT, Wheaton VI, Coughlin SR (1991) Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. Cell 64(6):1057–1068. 0092-8674(91)90261-V [pii]
Whelihan MF, Zachary V, Orfeo T, Mann KG (2012) Prothrombin activation in blood coagulation: the erythrocyte contribution to thrombin generation. Blood 120(18):3837–3845. https://doi.org/10.1182/blood-2012-05-427856. blood-2012-05-427856 [pii]
Wood JP, Silveira JR, Maille NM, Haynes LM, Tracy PB (2010) Prothrombin activation on the activated platelet surface optimizes expression of procoagulant activity. Blood 117:1710–1718. https://doi.org/10.1182/blood-2010-09-311035. blood-2010-09-311035 [pii]
Acknowledgments
We gratefully acknowledge Tracey Baird for her assistance with illustrations. Katherine Basore and Brock Summers at Washington University Center for Cellular Imaging provided expert assistance with the cryo-EM work. Cassandra Kukla and Sheila Rahman were involved in early developments of this article. This study was supported in part by the National Institutes of Health Research Grants HL049413, HL139554, and HL147821.
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Stojanovski, B.M., Mohammed, B.M., Di Cera, E. (2024). The Prothrombin-Prothrombinase Interaction. In: Harris, J.R., Marles-Wright, J. (eds) Macromolecular Protein Complexes V. Subcellular Biochemistry, vol 104. Springer, Cham. https://doi.org/10.1007/978-3-031-58843-3_15
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