F8 variant does not bind the cell membrane

Stable Identifier
R-HSA-9670189
Type
Reaction [transition]
Species
Homo sapiens
Compartment
Synonyms
FVIIIa does not associate with cell membrane
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Cleavage of factor VIII (FVIII) light chain promotes a change in the conformation of the C2 domain that facilitates dissociation from von Willebrand factor (VWF) and enhances the affinity of FVIIIa for anionic phospholipid surfaces (Saenko et al. 1998). Factors VIIIa associates with anionic phospholipid via a multistep process in which rapid association is followed by a slower step yielding higher affinity binding (Gilbert GE et al. 1990; Bardelle C et al. 1993). Crystallographic studies of the C2 domain of FVIII and two‐dimensional crystallography of FVIII bound to phospholipids identified multiple surface-exposed residues with hydrophobic and basic side chains that contribute to the electrostatic interaction with acidic phospholipid headgroups (Pratt KP et al. 1999; Stoilova‐McPhie S et al. 2002; Liu Z et al. 2010). Site‐directed mutatgenesis of residues believed to mediate FVIII binding to phospholipids confirmed the structural analysis findings (Gilbert GE et al. 2002, 2012). In addition, a membrane-binding motif on the FVIII C1 domain contributes to membrane binding and cofactor activity (Hsu TC et al. 2008; Meems H et al. 2009; Lü J et al. 2011). Further, high resolution crystal structures of the FVIII C2 domain also allowed modeling of hemophilic missense mutations in both the C1 and the C2 domains, which can indicate residues that are important for function or stability of the protein. (Liu ML et al. 2000; Spiegel PC et al. 2004). A change in the size or dimension of a single side chain may reduce the affinity of the interaction but is unlikely to completely prevent membrane binding (Liu ML 2000). Thus, a relatively small percentage of hemophilia A (HEMA)-associated mutations in the F8 gene has been reported to affect the membrane binding (Liu ML et al. 2000; Spiegel PC et al. 2004; Du J, et al. 2015). The Reactome event describes the defective interaction between the thrombin-activated FVIIIa protein and phospholipid membrane surfaces caused by HEMA-associated FVIII variants, such as A2220P, A2220del and Q2330P.

Literature References
PubMed ID Title Journal Year
25354705 Molecular simulation studies of human coagulation factor VIII C domain-mediated membrane binding

Du, J, Wichapong, K, Hackeng, KM, Nicolaes, GA

Thromb. Haemost. 2015
15471879 Surface-exposed hemophilic mutations across the factor VIII C2 domain have variable effects on stability and binding activities

Spiegel, PC, Murphy, P, Stoddard, BL

J. Biol. Chem. 2004
Participants
Participant Of
Normal reaction
Disease
Name Identifier Synonyms
factor VIII deficiency 12134 Congenital factor VIII disorder, Subhemophilia, Hemophilia A
Authored
Reviewed
Created
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