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FLASH GENE
Symbol F8 contributors: mct - updated : 22-02-2017
HGNC name coagulation factor VIII, procoagulant component (hemophilia A)
HGNC id 3546
PROTEIN
PHYSICAL PROPERTIES basic Hydrophobic
STRUCTURE
motifs/domains
  • a factor VIII C1b and C2 domains (cooperation between the C1 and C2 domains is necessary for full activity of the factor Xase complex) (
  • role of C1 domain is co-operative with other domains of the intact F8 molecule
  • a F8 A2 domain that is a key structural element
  • a motif implicated in cell adhesion
  • domain F5/8 type C2 responsible for phospholipid binding
  • three domain F5/8 type A composed of two plastocyanin-like repeats in each and two domains F5/8 type C, behind the hydrophobic surface lies a ring of positively charged residues
    • secondary structure
  • a beta sandwich core from which two beta turns and a loop display a group of solvent exposed hydrophobic residues
    • conjugated GlycoP
    isoforms Precursor undergoing multiple cleavage events, preprocoagulant component
    HOMOLOGY
    interspecies ortholog to murine F8
    Homologene
    FAMILY multicopper oxidase family
    CATEGORY regulatory
    SUBCELLULAR LOCALIZATION extracellular
        plasma membrane
    intracellular,cytoplasm,organelle,lumen
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,endoplasmic reticulum
    intracellular,cytoplasm,organelle,Golgi
    text synthetized and secreted by the liver
    basic FUNCTION
  • coagulation for FIXa which converts FX to FXa in presence of Ca2+ and phospholipids
  • key component of the fluid phase of the blood coagulation system
  • functions as a cofactor for Factor IXa in a membrane-bound enzyme complex
  • is a novel heme-binding protein
  • light chain of F8, which is not biologically active for clot formation, is sufficient for accelerating proteolytic cleavage of VWF by ADAMTS13 under fluid shear stress and (patho) physiological conditions
  • may be involved in regulating VWF homeostasis under physiological conditions
  • role for F8 and thrombin/F2R in regulating hematopoiesis and its interplay with the bone structure
  • F8 stability and half-life is dependent on non-covalent complex formation with von Willebrand factor (VWF) to avoid proteolysis and clearance
  • glycoprotein cofactor that is essential for the intrinsic pathway of the blood coagulation cascade
    • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS coagulation/hemostasis
    text intrinsic pathway of blood coagulation
    PATHWAY
    metabolism
    signaling
    a component
  • active cofactor, FVIIIa is a trimer composed of A1, A2 and A3-C1-C2 subunits (its role is to markedly increase the catalytic efficiency of factor IXa)
  • circulates as a heterodimer composed of heavy (A1A2B domains) and light (A3C1C2 domains) chains
    • INTERACTION
    DNA
    RNA
    small molecule metal binding, other,
  • calcium Ca2+
  • phospholipids
  • activated protein held in a complex with Cu++
    • protein
  • variant 1 associating with vWF (von Willebrand factor) in a covalent complex
  • interacting with MCFD2 and LMAN1, forming stable complexes in liver cells
  • binds to phosphatidylserine (PS)-containing membranes through its tandem, lectin-homology, C1 and C2 domains
  • F8 accelerates proteolytic cleavage of VWF by ADAMTS13 under fluid shear stress
  • light chain, particularly the a3 region in the light chain of F8, contains the major binding site for VWF
  • LMAN1 transports coagulation factors V (F5) and VIII (F8)
  • LDLR was shown to mediate clearance of blood coagulation factor VIII (F8) from the circulation
  • hydrophobic helical stack between the GLA and EGF1 domains of F9 is predicted to be primary interacting region with the A3-C2 domain interface of F8
  • LRP1 mediates clearance of blood coagulation factor VIII (F8)
  • F8 interacts likely with LRP1 via an extended surface of multiple lysine residues that starts at the bottom of the C1 domain and winds around the F8 molecule
  • VWF modulates the internalization and presentation of F8-derived peptides on major histocompatibility complex class II
    • cell & other
    REGULATION
    activated by by thrombin to form a non-covalently linked A1/A2/A3-C1-C2 heterotrimer
    Other VWF may reduce the immunogenicity of F8 by inhibiting the uptake of F8 by antigen presenting cells, the first step in the development of an immune response against a foreign antigen
    ASSOCIATED DISORDERS
    corresponding disease(s) F8D , DUPXQ28D
    related resource The Haemophilia A Mutation, Structure, Test and Resource Site (HAMSTeRS)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --over  
    FVIII levels above the 75(th) percentile are associated with a significant odds ratio for the occurrence of venous thromboembolism
    Susceptibility risk factor for venous thromboembolism
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target use of VWF in conjunction with F8 in the management of patients with haemophilia A (Lacroix-Desmazes 2008)
    ANIMAL & CELL MODELS
  • multiple eye defects and developmental alteractions in chimeric and transgenic mice are produced by a motif implicated in cell adhesion
  • F VIII deficient mice (Vanden Driessche, 99)
  • endothelial cells from multiple, but not all, tissues contribute to the plasma F8 pool in the mouse