Factor IX

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Coagulation factor IX
PDB 1pfx EBI.jpg
PDB rendering based on 1pfx.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols F9 ; FIX; HEMB; P19; PTC; THPH8
External IDs OMIM300746 MGI88384 HomoloGene106 ChEMBL: 2016 GeneCards: F9 Gene
EC number 3.4.21.22
RNA expression pattern
PBB GE F9 207218 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 2158 14071
Ensembl ENSG00000101981 ENSMUSG00000031138
UniProt P00740 P16294
RefSeq (mRNA) NM_000133 NM_007979
RefSeq (protein) NP_000124 NP_032005
Location (UCSC) Chr X:
138.61 – 138.65 Mb
Chr X:
60 – 60.03 Mb
PubMed search [1] [2]

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.[1]

Physiology[edit]

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.[2][3] 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.[2]

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.[4]

Domain architecture[edit]

Factors VII, IX, and X all play key roles in blood coagulation and also share a common domain architecture.[5] The factor IX protein is composed of four protein domains. These are 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.[5] 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.[6]

The structures of all four domains have been solved. A structure of the two EGF domains and trypsin like domain was determined for the pig protein.[7] The structure of the Gla domain, which is responsible for Ca(II)-dependent phospholipid binding, was also determined by NMR.[8]

Several structures of 'super active' mutants have been solved [9] which reveal the nature of Factor IX activation by other proteins in the clotting cascade.

Genetics[edit]

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.[10]

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.[11]

Role in disease[edit]

Deficiency of factor IX causes Christmas disease (hemophilia B).[1] 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.[12] Recombinant factor IX is used to treat Christmas disease, and is commercially available as BeneFIX[13] and Alprolix.[14] Some rare mutations of factor IX result in elevated clotting activity, and can result in clotting diseases, such as deep vein thrombosis.[15]

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.[16]

A list of all the mutations in Factor IX is compiled and maintained at the Factor IX mutation database[17] maintained at the University College London.

References[edit]

  1. ^ a b Biggs, R; Douglas, AS; MacFarlane, RG; Dacie, JV; Pitney, WR; Merskey, C.; O'Brien, J. R. (1952). "Christmas Disease". British Medical Journal 2 (4799): 1378–82. doi:10.1136/bmj.2.4799.1378. PMC 2022306. PMID 12997790. 
  2. ^ a b Di Scipio RG, Kurachi K, Davie EW (June 1978). "Activation of human factor IX (Christmas factor)". J. Clin. Invest. 61 (6): 1528–38. doi:10.1172/JCI109073. PMC 372679. PMID 659613. 
  3. ^ Taran LD (July 1997). "Factor IX of the blood coagulation system: a review". Biochemistry Mosc. 62 (7): 685–93. PMID 9331959. 
  4. ^ Boland EJ, Liu YC, Walter CA, Herbert DC, Weaker FJ, Odom MW, Jagadeeswaran P (1995). "Age-specific regulation of clotting factor IX gene expression in normal and transgenic mice". Blood 86 (6): 2198–205. PMID 7662969. 
  5. ^ a b Zhong D, Bajaj MS, Schmidt AE, Bajaj SP (February 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". J. Biol. Chem. 277 (5): 3622–31. doi:10.1074/jbc.M111202200. PMID 11723140. 
  6. ^ Wilkinson FH, Ahmad SS, Walsh PN (February 2002). "The factor IXa second epidermal growth factor (EGF2) domain mediates platelet binding and assembly of the factor X activating complex". J. Biol. Chem. 277 (8): 5734–41. doi:10.1074/jbc.M107753200. PMID 11714704. 
  7. ^ Brandstetter H, Bauer M, Huber R, Lollar P, Bode W (October 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): 9796–800. doi:10.1073/pnas.92.21.9796. PMC 40889. PMID 7568220. 
  8. ^ Freedman SJ, Furie BC, Furie B, Baleja JD (September 1995). "Structure of the calcium ion-bound gamma-carboxyglutamic acid-rich domain of factor IX". Biochemistry 34 (38): 12126–37. doi:10.1021/bi00038a005. PMID 7547952. 
  9. ^ Zogg T, Brandstetter H, (2009). "Structural Basis of the Cofactor- and Substrate-Assisted Activation of Human Coagulation Factor Ixa". Structure 17 (12): 1669–1678. doi:10.1016/j.str.2009.10.011. PMID 20004170. 
  10. ^ Kurachi K, Davie E (1982). "Isolation and characterization of a cDNA coding for human factor IX". Proc Natl Acad Sci USA 79 (21): 6461–4. doi:10.1073/pnas.79.21.6461. PMC 347146. PMID 6959130. 
  11. ^ Nicholl D. (2002). An Introduction to Genetic Engineering Second Edition. Cambridge University Press. p. 257. 
  12. ^ Taylor, S. A.; Duffin, J.; Cameron, C.; Teitel, J.; Garvey, B.; Lillicrap, D. P. (1992). "Characterization of the original Christmas disease mutation (cysteine 206----serine): From clinical recognition to molecular pathogenesis". Thrombosis and haemostasis 67 (1): 63–65. PMID 1615485.  edit
  13. ^ "Home: BeneFIX Coagulation Factor IX (Recombinant) Official Site". 
  14. ^ "Home: Alprolix [Coagulation Factor IX (Recombinant), Fc Fusion Protein] Official Site". 
  15. ^ Simioni P, Tormene D, Tognin G, Gavasso S, Bulato C, Iacobelli NP, Finn JD, Spiezia L, Radu C, Arruda VR (October 2009). "X-linked thrombophilia with a mutant factor IX (factor IX Padua)". N. Engl. J. Med. 361 (17): 1671–5. doi:10.1056/NEJMoa0904377. PMID 19846852. 
  16. ^ Rossi M, Jayaram R, Sayeed R (September 2011). "Do patients with haemophilia undergoing cardiac surgery have good surgical outcomes?". Interact Cardiovasc Thorac Surg 13 (3): 320–31. doi:10.1510/icvts.2011.272401. PMID 21712351. 
  17. ^ "Home: Factor IX Mutation Database". 

Further reading[edit]

External links[edit]