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Structural basis of the cofactor- and substrate-assisted activation of human coagulation factor IXa.

Zögg T, Brandstetter H
Structure 17 1669-1678 (2009)
Related entries: 2wph, 2wpi, 2wpk, 2wpl, 2wpm

Cited: 33 times
EuropePMC logo PMID: 20004170

Abstract

Human coagulation factor IX serves both to maintain and to control blood coagulation. The dual function of this hemophilic factor is implemented by a tiered activation mechanism. Processed two-chain factor IXa is catalytically silent; only together with its cofactor VIIIa does factor IXa form the highly potent Xase complex. The detailed mechanism of this secondary activation has remained elusive so far. Here we present the crystal structures of Xase-like factor IXa mutants with several-thousand-fold activity enhancement that mimic the secondary activation by Xase formation. The structures reveal how cofactor-triggered and substrate-assisted modulations in the factor IXa 99- and 60-loops cooperate in S4 through S2' formation, allowing for productive substrate recognition. We could further physically map and visualize a distinct communication line, along which agonists such as Ca(2+) direct their effects to the active site and vice versa.

Articles - 2wpj mentioned but not cited (2)

  1. Single synonymous mutation in factor IX alters protein properties and underlies haemophilia B. Simhadri VL, Hamasaki-Katagiri N, Lin BC, Hunt R, Jha S, Tseng SC, Wu A, Bentley AA, Zichel R, Lu Q, Zhu L, Freedberg DI, Monroe DM, Sauna ZE, Peters R, Komar AA, Kimchi-Sarfaty C. J Med Genet 54 338-345 (2017)
  2. Sodium-site in serine protease domain of human coagulation factor IXa: evidence from the crystal structure and molecular dynamics simulations study. Vadivel K, Schreuder HA, Liesum A, Schmidt AE, Goldsmith G, Bajaj SP. J Thromb Haemost 17 574-584 (2019)


Reviews citing this publication (2)

  1. Surface loops of trypsin-like serine proteases as determinants of function. Goettig P, Brandstetter H, Magdolen V. Biochimie 166 52-76 (2019)
  2. The Molecular Basis of FIX Deficiency in Hemophilia B. Shen G, Gao M, Cao Q, Li W. Int J Mol Sci 23 2762 (2022)

Articles citing this publication (29)

  1. An interactive mutation database for human coagulation factor IX provides novel insights into the phenotypes and genetics of hemophilia B. Rallapalli PM, Kemball-Cook G, Tuddenham EG, Gomez K, Perkins SJ. J Thromb Haemost 11 1329-1340 (2013)
  2. An improved yeast surface display platform for the screening of nanobody immune libraries. Uchański T, Zögg T, Yin J, Yuan D, Wohlkönig A, Fischer B, Rosenbaum DM, Kobilka BK, Pardon E, Steyaert J. Sci Rep 9 382 (2019)
  3. N-terminal protein modification by substrate-activated reverse proteolysis. Liebscher S, Schöpfel M, Aumüller T, Sharkhuukhen A, Pech A, Höss E, Parthier C, Jahreis G, Stubbs MT, Bordusa F. Angew Chem Int Ed Engl 53 3024-3028 (2014)
  4. Crystal structure and substrate-induced activation of ADAMTS13. Petri A, Kim HJ, Xu Y, de Groot R, Li C, Vandenbulcke A, Vanhoorelbeke K, Emsley J, Crawley JTB. Nat Commun 10 3781 (2019)
  5. Engineered factor IX variants bypass FVIII and correct hemophilia A phenotype in mice. Milanov P, Ivanciu L, Abriss D, Quade-Lyssy P, Miesbach W, Alesci S, Tonn T, Grez M, Seifried E, Schüttrumpf J. Blood 119 602-611 (2012)
  6. Evidence of the E*-E equilibrium from rapid kinetics of Na+ binding to activated protein C and factor Xa. Vogt AD, Bah A, Di Cera E. J Phys Chem B 114 16125-16130 (2010)
  7. Rigidification of the autolysis loop enhances Na(+) binding to thrombin. Pozzi N, Chen R, Chen Z, Bah A, Di Cera E. Biophys Chem 159 6-13 (2011)
  8. Crystal structures of the viral protease Npro imply distinct roles for the catalytic water in catalysis. Zögg T, Sponring M, Schindler S, Koll M, Schneider R, Brandstetter H, Auer B. Structure 21 929-938 (2013)
  9. Do-it-yourself histidine-tagged bovine enterokinase: a handy member of the protein engineer's toolbox. Skala W, Goettig P, Brandstetter H. J Biotechnol 168 421-425 (2013)
  10. A factor VIIIa-mimetic bispecific antibody, Mim8, ameliorates bleeding upon severe vascular challenge in hemophilia A mice. Østergaard H, Lund J, Greisen PJ, Kjellev S, Henriksen A, Lorenzen N, Johansson E, Røder G, Rasch MG, Johnsen LB, Egebjerg T, Lund S, Rahbek-Nielsen H, Gandhi PS, Lamberth K, Loftager M, Andersen LM, Bonde AC, Stavenuiter F, Madsen DE, Li X, Holm TL, Ley CD, Thygesen P, Zhu H, Zhou R, Thorn K, Yang Z, Hermit MB, Bjelke JR, Hansen BG, Hilden I. Blood 138 1258-1268 (2021)
  11. Molecular Basis of Enhanced Activity in Factor VIIa-Trypsin Variants Conveys Insights into Tissue Factor-mediated Allosteric Regulation of Factor VIIa Activity. Sorensen AB, Madsen JJ, Svensson LA, Pedersen AA, Østergaard H, Overgaard MT, Olsen OH, Gandhi PS. J Biol Chem 291 4671-4683 (2016)
  12. Selective disruption of heparin and antithrombin-mediated regulation of human factor IX. Westmark PR, Tanratana P, Sheehan JP. J Thromb Haemost 13 1053-1063 (2015)
  13. Elevated Plasma Factor IXa Activity in Premenopausal Women on Hormonal Contraception. Tanratana P, Ellery P, Westmark P, Mast AE, Sheehan JP. Arterioscler Thromb Vasc Biol 38 266-274 (2018)
  14. Mutational Profiles of F8 and F9 in a Cohort of Haemophilia A and Haemophilia B Patients in the Multi-ethnic Malaysian Population. Zahari M, Sulaiman SA, Othman Z, Ayob Y, Karim FA, Jamal R. Mediterr J Hematol Infect Dis 10 e2018056 (2018)
  15. Next generation FIX muteins with FVIII-independent activity for alternative treatment of hemophilia A. Quade-Lyssy P, Abriss D, Milanov P, Ungerer C, Königs C, Seifried E, Schüttrumpf J. J Thromb Haemost 12 1861-1873 (2014)
  16. Residues of the 39-loop restrict the plasma inhibitor specificity of factor IXa. Yang L, Rezaie AR. J Biol Chem 288 12692-12698 (2013)
  17. Sirtilins - the new old members of the vitamin K-dependent coagulation factor family. Dahms SO, Demir F, Huesgen PF, Thorn K, Brandstetter H. J Thromb Haemost 17 470-481 (2019)
  18. Structural determinants of specificity and regulation of activity in the allosteric loop network of human KLK8/neuropsin. Debela M, Magdolen V, Skala W, Elsässer B, Schneider EL, Craik CS, Biniossek ML, Schilling O, Bode W, Brandstetter H, Goettig P. Sci Rep 8 10705 (2018)
  19. Coagulation factor IX regulates cell migration and adhesion in vitro. Kitano H, Mamiya A, Tomomi I, Shinichiro K, Chiaki H. Cell Biol Int 39 1162-1172 (2015)
  20. Exosite binding drives substrate affinity for the activation of coagulation factor X by the intrinsic Xase complex. Basavaraj MG, Krishnaswamy S. J Biol Chem 295 15198-15207 (2020)
  21. Plasmin-mediated proteolysis of human factor IXa in the presence of calcium/phospholipid: Conversion of procoagulant factor IXa to a fibrinolytic enhancer. Schmidt AE, Vadivel K, Whitelegge J, Bajaj SP. J Thromb Haemost 18 1171-1182 (2020)
  22. Probing activation-driven changes in coagulation factor IX by mass spectrometry. Freato N, van Alphen FPJ, Boon-Spijker M, van den Biggelaar M, Meijer AB, Mertens K, Ebberink EHTM. J Thromb Haemost 19 1447-1459 (2021)
  23. Quantifying vitamin K-dependent holoprotein compaction caused by differential γ-carboxylation using high-pressure size exclusion chromatography. Vanderslice NC, Messer AS, Vadivel K, Bajaj SP, Phillips M, Fatemi M, Xu W, Velander WH. Anal Biochem 479 6-14 (2015)
  24. A systematic approach for evaluating the role of surface-exposed loops in trypsin-like serine proteases applied to the 170 loop in coagulation factor VIIa. Sorensen AB, Greisen PJ, Madsen JJ, Lund J, Andersen G, Wulff-Larsen PG, Pedersen AA, Gandhi PS, Overgaard MT, Østergaard H, Olsen OH. Sci Rep 12 3747 (2022)
  25. Correlation of factor IXa subsite modulations with effects on substrate discrimination. Neuenschwander PF, Deadmond KJ, Zepeda K, Rutland J. J Thromb Haemost 10 382-389 (2012)
  26. Maturation of coagulation factor IX during Xase formation as deduced using factor VIII-derived peptides. Fang H, Zögg T, Brandstetter H. FEBS Open Bio 9 1370-1378 (2019)
  27. Coagulation factor IX analysis in bioreactor cell culture supernatant predicts quality of the purified product. Zacchi LF, Roche-Recinos D, Pegg CL, Phung TK, Napoli M, Aitken C, Sandford V, Mahler SM, Lee YY, Schulz BL, Howard CB. Commun Biol 4 390 (2021)
  28. FIXing factor VIII inhibitors. Ponder KP. Blood 119 325-326 (2012)
  29. SAXS analysis of the intrinsic tenase complex bound to a lipid nanodisc highlights intermolecular contacts between factors VIIIa/IXa. Childers KC, Peters SC, Lollar P, Spencer HT, Doering CB, Spiegel PC. Blood Adv 6 3240-3254 (2022)


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