| F9 |
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| Available structures |
| PDB |
Ortholog search: PDBe RCSB |
| List of PDB id codes |
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1CFH, 1CFI, 1EDM, 1IXA, 1MGX, 1NL0, 1RFN, 2WPH, 2WPI, 2WPJ, 2WPK, 2WPL, 2WPM, 3KCG, 3LC3, 3LC5, 4YZU, 4Z0K, 4ZAE, 4WM0, 4WMA, 4WMI, 4WMK, 4WN2, 4WNH, 5EGM, 5JBC, 5JB9, 5JBB, 5JB8, 5JBA
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| Identifiers |
| Aliases |
F9, F9 p22, FIX, HEMB, P19, PTC, THPH8, coagulation factor IX |
| External IDs |
OMIM: 300746 MGI: 88384 HomoloGene: 106 GeneCards: F9 |
| Gene ontology |
| Molecular function |
• endopeptidase activity
• metal ion binding
• peptidase activity
• serine-type peptidase activity
• hydrolase activity
• calcium ion binding
• serine-type endopeptidase activity
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| Cellular component |
• endoplasmic reticulum lumen
• plasma membrane
• Golgi lumen
• extracellular exosome
• extracellular region
• extracellular space
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| Biological process |
• hemostasis
• blood coagulation, intrinsic pathway
• zymogen activation
• ER to Golgi vesicle-mediated transport
• signal peptide processing
• blood coagulation, extrinsic pathway
• peptidyl-glutamic acid carboxylation
• proteolysis
• blood coagulation
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| Sources:Amigo / QuickGO |
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| RNA expression pattern |
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| More reference expression data |
| Orthologs |
| Species |
Human |
Mouse |
| Entrez |
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| Ensembl |
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| UniProt |
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| RefSeq (mRNA) |
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| RefSeq (protein) |
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| Location (UCSC) |
Chr X: 139.53 – 139.56 Mb |
Chr X: 60 – 60.03 Mb |
| PubMed search |
[1] |
[2] |
| Wikidata |
| View/Edit Human |
View/Edit Mouse |
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Factor IX (or Christmas factor) (EC 3.4.21.22) is one of the serine proteases of the coagulation system; it belongs to peptidase family S1. Deficiency of this protein causes hemophilia B. It was discovered in 1952 after a young boy named Stephen Christmas was found to be lacking this exact factor, leading to hemophilia.[3]
Factor IX complex is on the WHO Model List of Essential Medicines, the most important medications needed in a basic health system.[4]
Contents
- 1 Physiology
- 2 Domain architecture
- 3 Genetics
- 4 Role in disease
- 5 References
- 6 Further reading
- 7 External links
Physiology
The blood coagulation and Protein C pathway.
Factor IX is produced as a zymogen, an inactive precursor. It is processed to remove the signal peptide, glycosylated and then cleaved by factor XIa (of the contact pathway) or factor VIIa (of the tissue factor pathway) to produce a two-chain form where the chains are linked by a disulfide bridge.[5][6] When activated into factor IXa, in the presence of Ca2+, membrane phospholipids, and a Factor VIII cofactor, it hydrolyses one arginine-isoleucine bond in factor X to form factor Xa.
Factor IX is inhibited by antithrombin.[5]
Factor IX expression increases with age in humans and mice. In mouse models mutations within the promoter region of factor IX have an age-dependent phenotype.[7]
Domain architecture
Factors VII, IX, and X all play key roles in blood coagulation and also share a common domain architecture.[8] The factor IX protein is composed of four protein domains: the Gla domain, two tandem copies of the EGF domain and a C-terminal trypsin-like peptidase domain which carries out the catalytic cleavage.
Human factor IX protein domain architecture, where each protein domain is represented by a coloured box
The N-terminal EGF domain has been shown to at least in part be responsible for binding tissue factor.[8] Wilkinson et al. conclude that residues 88 to 109 of the second EGF domain mediate binding to platelets and assembly of the factor X activating complex.[9]
The structures of all four domains have been solved. A structure of the two EGF domains and the trypsin-like domain was determined for the pig protein.[10] The structure of the Gla domain, which is responsible for Ca(II)-dependent phospholipid binding, was also determined by NMR.[11]
Several structures of 'super active' mutants have been solved,[12] which reveal the nature of factor IX activation by other proteins in the clotting cascade.
Genetics
In human, the F9 gene is located on the X chromosome at position q27.1.
The gene for factor IX is located on the X chromosome (Xq27.1-q27.2) and is therefore X-linked recessive: mutations in this gene affect males much more frequently than females. It was first cloned in 1982 by Kotoku Kurachi and Earl Davie.[13]
Polly, a transgenic cloned Poll Dorset sheep carrying the gene for factor IX, was produced by Dr Ian Wilmut at the Roslin Institute in 1997.[14]
Role in disease
Deficiency of factor IX causes Christmas disease (hemophilia B).[3] Over 100 mutations of factor IX have been described; some cause no symptoms, but many lead to a significant bleeding disorder. The original Christmas disease mutation was identified by sequencing of Christmas' DNA, revealing a mutation which changed a cysteine to a serine.[15] Recombinant factor IX is used to treat Christmas disease. Formulations include:
- nonacog alfa (trade name BeneFix)[16]
- albutrepenonacog alfa (trade name Idelvion)[17]
- eftrenonacog alfa (trade name Alprolix)[18]
Some rare mutations of factor IX result in elevated clotting activity, and can result in clotting diseases, such as deep vein thrombosis.[19]
Factor IX deficiency is treated by injection of purified factor IX produced through cloning in various animal or animal cell vectors. Tranexamic acid may be of value in patients undergoing surgery who have inherited factor IX deficiency in order to reduce the perioperative risk of bleeding.[20]
A list of all the mutations in Factor IX is compiled and maintained at the Factor IX mutation database[21] maintained at the University College London.
References
- ^ "Human PubMed Reference:".
- ^ "Mouse PubMed Reference:".
- ^ a b Biggs R, Douglas AS, Macfarlane RG, Dacie JV, Pitney WR (Dec 1952). "Christmas disease: a condition previously mistaken for haemophilia". British Medical Journal. 2 (4799): 1378–82. PMC 2022306 . PMID 12997790. doi:10.1136/bmj.2.4799.1378.
- ^ "19th WHO Model List of Essential Medicines (April 2015)" (PDF). WHO. April 2015. Retrieved May 10, 2015.
- ^ a b Di Scipio RG, Kurachi K, Davie EW (Jun 1978). "Activation of human factor IX (Christmas factor)". The Journal of Clinical Investigation. 61 (6): 1528–38. PMC 372679 . PMID 659613. doi:10.1172/JCI109073.
- ^ Taran LD (Jul 1997). "Factor IX of the blood coagulation system: a review". Biochemistry. Biokhimii͡A. 62 (7): 685–93. PMID 9331959.
- ^ Boland EJ, Liu YC, Walter CA, Herbert DC, Weaker FJ, Odom MW, Jagadeeswaran P (Sep 1995). "Age-specific regulation of clotting factor IX gene expression in normal and transgenic mice". Blood. 86 (6): 2198–205. PMID 7662969.
- ^ a b Zhong D, Bajaj MS, Schmidt AE, Bajaj SP (Feb 2002). "The N-terminal epidermal growth factor-like domain in factor IX and factor X represents an important recognition motif for binding to tissue factor". The Journal of Biological Chemistry. 277 (5): 3622–31. PMID 11723140. doi:10.1074/jbc.M111202200.
- ^ Wilkinson FH, Ahmad SS, Walsh PN (Feb 2002). "The factor IXa second epidermal growth factor (EGF2) domain mediates platelet binding and assembly of the factor X activating complex". The Journal of Biological Chemistry. 277 (8): 5734–41. PMID 11714704. doi:10.1074/jbc.M107753200.
- ^ Brandstetter H, Bauer M, Huber R, Lollar P, Bode W (Oct 1995). "X-ray structure of clotting factor IXa: active site and module structure related to Xase activity and hemophilia B". Proceedings of the National Academy of Sciences of the United States of America. 92 (21): 9796–800. PMC 40889 . PMID 7568220. doi:10.1073/pnas.92.21.9796.
- ^ Freedman SJ, Furie BC, Furie B, Baleja JD (Sep 1995). "Structure of the calcium ion-bound gamma-carboxyglutamic acid-rich domain of factor IX". Biochemistry. 34 (38): 12126–37. PMID 7547952. doi:10.1021/bi00038a005.
- ^ Zögg T, Brandstetter H (Dec 2009). "Structural basis of the cofactor- and substrate-assisted activation of human coagulation factor IXa". Structure. 17 (12): 1669–78. PMID 20004170. doi:10.1016/j.str.2009.10.011.
- ^ Kurachi K, Davie EW (Nov 1982). "Isolation and characterization of a cDNA coding for human factor IX". Proceedings of the National Academy of Sciences of the United States of America. 79 (21): 6461–4. PMC 347146 . PMID 6959130. doi:10.1073/pnas.79.21.6461.
- ^ Nicholl D. (2002). An Introduction to Genetic Engineering Second Edition. Cambridge University Press. p. 257.
- ^ Taylor SA, Duffin J, Cameron C, Teitel J, Garvey B, Lillicrap DP (Jan 1992). "Characterization of the original Christmas disease mutation (cysteine 206----serine): from clinical recognition to molecular pathogenesis". Thrombosis and Haemostasis. 67 (1): 63–5. PMID 1615485.
- ^ "Home: BeneFIX Coagulation Factor IX (Recombinant) Official Site".
- ^ EMA: Idelvion
- ^ "Home: Alprolix [Coagulation Factor IX (Recombinant), Fc Fusion Protein] Official Site".
- ^ Simioni P, Tormene D, Tognin G, Gavasso S, Bulato C, Iacobelli NP, Finn JD, Spiezia L, Radu C, Arruda VR (Oct 2009). "X-linked thrombophilia with a mutant factor IX (factor IX Padua)". The New England Journal of Medicine. 361 (17): 1671–5. PMID 19846852. doi:10.1056/NEJMoa0904377.
- ^ Rossi M, Jayaram R, Sayeed R (Sep 2011). "Do patients with haemophilia undergoing cardiac surgery have good surgical outcomes?". Interactive Cardiovascular and Thoracic Surgery. 13 (3): 320–31. PMID 21712351. doi:10.1510/icvts.2011.272401.
- ^ "Home: Factor IX Mutation Database".
Further reading
- Davie EW, Fujikawa K (1975). "Basic mechanisms in blood coagulation". Annual Review of Biochemistry. 44: 799–829. PMID 237463. doi:10.1146/annurev.bi.44.070175.004055.
- Sommer SS (Jul 1992). "Assessing the underlying pattern of human germline mutations: lessons from the factor IX gene". FASEB Journal. 6 (10): 2767–74. PMID 1634040.
- Lenting PJ, van Mourik JA, Mertens K (Dec 1998). "The life cycle of coagulation factor VIII in view of its structure and function". Blood. 92 (11): 3983–96. PMID 9834200.
- Lowe GD (Dec 2001). "Factor IX and thrombosis". British Journal of Haematology. 115 (3): 507–13. PMID 11736930. doi:10.1046/j.1365-2141.2001.03186.x.
- O'Connell NM (Jun 2003). "Factor XI deficiency--from molecular genetics to clinical management". Blood Coagulation & Fibrinolysis. 14 Suppl 1: S59–64. PMID 14567539. doi:10.1097/00001721-200306001-00014.
- Du X (May 2007). "Signaling and regulation of the platelet glycoprotein Ib-IX-V complex". Current Opinion in Hematology. 14 (3): 262–9. PMID 17414217. doi:10.1097/MOH.0b013e3280dce51a.
External links
- GeneReviews/NCBI/NIH/UW entry on Hemophilia B
- The MEROPS online database for peptidases and their inhibitors: S01.214
- An X(-mas) Factor that gets our vote- QUite Interesting PDB Structure article at PDBe
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PDB gallery
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1cfh: STRUCTURE OF THE METAL-FREE GAMMA-CARBOXYGLUTAMIC ACID-RICH MEMBRANE BINDING REGION OF FACTOR IX BY TWO-DIMENSIONAL NMR SPECTROSCOPY
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1cfi: NMR STRUCTURE OF CALCIUM ION-BOUND GAMMA-CARBOXY-GLUTAMIC ACID-RICH DOMAIN OF FACTOR IX
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1edm: EPIDERMAL GROWTH FACTOR-LIKE DOMAIN FROM HUMAN FACTOR IX
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1ixa: THE THREE-DIMENSIONAL STRUCTURE OF THE FIRST EGF-LIKE MODULE OF HUMAN FACTOR IX: COMPARISON WITH EGF AND TGF-A
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1j34: Crystal Structure of Mg(II)-and Ca(II)-bound Gla Domain of Factor IX Complexed with Binding Protein
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1j35: Crystal Structure of Ca(II)-bound Gla Domain of Factor IX Complexed with Binding Protein
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1mgx: COAGULATION FACTOR, MG(II), NMR, 7 STRUCTURES (BACKBONE ATOMS ONLY)
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1nl0: Crystal structure of human factor IX Gla domain in complex of an inhibitory antibody, 10C12
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1rfn: HUMAN COAGULATION FACTOR IXA IN COMPLEX WITH P-AMINO BENZAMIDINE
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Proteins involved in coagulation
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| Coagulation factors |
| Primary hemostasis |
- vWF
- platelet membrane glycoproteins: Ib (A
- B
- IX)
- IIb/IIIa (IIb
- IIIa)
- VI
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| Intrinsic pathway |
- HMWK/Bradykinin
- Prekallikrein/Kallikrein
- XII "Hageman"
- XI
- IX
- VIII
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| Extrinsic pathway |
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| Common pathway |
- X
- V
- II "(Pro)thrombin"
- I "Fibrin"
- Fibrinogen (FGA, FGG)
- XIII
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| Coagulation inhibitors |
- Antithrombin (inhibits II, IX, X, XI, XII)
- Protein C (inhibits V, VIII)/Protein S (cofactor for protein C)
- Protein Z (inhibits X)
- ZPI (inhibits X, XI)
- TFPI (inhibits III)
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| Thrombolysis/fibrinolysis |
- Plasmin
- tPA/urokinase
- PAI-1/2
- α2-AP
- α2-macroglobulin
- TAFI
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Endopeptidases: serine proteases/serine endopeptidases (EC 3.4.21)
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| Digestive enzymes |
- Enteropeptidase
- Trypsin
- Chymotrypsin
- Elastase
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| Coagulation |
- factors: Thrombin
- Factor VIIa
- Factor IXa
- Factor Xa
- Factor XIa
- Factor XIIa
- Kallikrein
- PSA
- KLK1
- KLK2
- KLK3
- KLK4
- KLK5
- KLK6
- KLK7
- KLK8
- KLK9
- KLK10
- KLK11
- KLK12
- KLK13
- KLK14
- KLK15
- fibrinolysis: Plasmin
- Plasminogen activator
- Tissue plasminogen activator
- Urinary plasminogen activator
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| Complement system |
- Factor B
- Factor D
- Factor I
- MASP
- C3-convertase
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| Other immune system |
- Chymase
- Granzyme
- Tryptase
- Proteinase 3/Myeloblastin
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| Venombin |
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| Other |
- Acrosin
- Prolyl endopeptidase
- Pronase
- Proprotein convertases
- Prostasin
- Reelin
- Subtilisin/Furin
- Streptokinase
- S1P
- Cathepsin
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Enzymes
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| Activity |
- Active site
- Binding site
- Catalytic triad
- Oxyanion hole
- Enzyme promiscuity
- Catalytically perfect enzyme
- Coenzyme
- Cofactor
- Enzyme catalysis
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| Regulation |
- Allosteric regulation
- Cooperativity
- Enzyme inhibitor
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| Classification |
- EC number
- Enzyme superfamily
- Enzyme family
- List of enzymes
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| Kinetics |
- Enzyme kinetics
- Eadie–Hofstee diagram
- Hanes–Woolf plot
- Lineweaver–Burk plot
- Michaelis–Menten kinetics
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| Types |
- EC1 Oxidoreductases (list)
- EC2 Transferases (list)
- EC3 Hydrolases (list)
- EC4 Lyases (list)
- EC5 Isomerases (list)
- EC6 Ligases (list)
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