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Details on Person Post-translational cellular processing of the factor VIII (F...
| Class:Id | Summation:9668149 |
|---|---|
| _displayName | Post-translational cellular processing of the factor VIII (F... |
| _timestamp | 2020-01-13 20:26:29 |
| created | [InstanceEdit:9668147] Shamovsky, Veronica, 2019-11-19 |
| literatureReference | [LiteratureReference:9662010] Molecular characterization of severe hemophilia A suggests that about half the mutations are not within the coding regions and splice junctions of the factor VIII gene [LiteratureReference:9668041] Identification and functional importance of tyrosine sulfate residues within recombinant factor VIII [LiteratureReference:9668032] Identification of individual tyrosine sulfation sites within factor VIII required for optimal activity and efficient thrombin cleavage [LiteratureReference:9667090] Interaction Between the a3 Region of Factor VIII and the TIL'E' Domains of the von Willebrand Factor [LiteratureReference:9668020] Sulfation of Tyr1680 of human blood coagulation factor VIII is essential for the interaction of factor VIII with von Willebrand factor [LiteratureReference:9661636] Storage and regulated secretion of factor VIII in blood outgrowth endothelial cells [LiteratureReference:9668055] Characterization of tyrosine sulfate residues in antihemophilic recombinant factor VIII by liquid chromatography electrospray ionization tandem mass spectrometry and amino acid analysis [LiteratureReference:9668038] Physicochemical characterisation of rVIII-SingleChain, a novel recombinant single-chain factor VIII |
| modified | [InstanceEdit:9668387] Shamovsky, Veronica, 2019-11-25 [InstanceEdit:9672406] Shamovsky, Veronica, 2019-12-25 [InstanceEdit:9674513] Shamovsky, Veronica, 2020-01-13 |
| text | Post-translational cellular processing of the factor VIII (FVIII or F8) precursor enables O-sulfation of tyrosine residues (Pittman DD et al. 1992; Michnick DA et al. 1994). Biochemical and structural studies demonstrated that human FVIII contains six potential tyrosine sulfation sites on the FVIII molecule, ie, four on the heavy chain (at amino acid residues 365, 737, 738, and 742) and two in the a3 subdomain of the light chain (residues 1683 and 1699) (Pittman DD et al. 1992; Michnick DA et al. 1994; Severs JC et al. 1999; Schmidbauer S et al. 2015). Site-directed mutagenesis of individual or multiple tyrosine residues showed that all the six sulfation sites are required to modulate FVIII activity (Pittman DD et al. 1992; Michnick DA et al. 1994). Further, mutagenesis of Tyr1699 to Phe (Y1699F) demonstrated that sulfation at that residue was required for high affinity interaction of FVIII with von Willebrand factor (vWF) (Leyte A et al. 1991). In the absence of tyrosine sulfation at 1699 in FVIII, the affinity for vWF was reduced by 5-fold (Leyte A et al. 1991). Nuclear magnetic resonance (NMR) spectrum studies of the complex between FVIII and vWF showed significantly larger residue-specific chemical shift changes when Y1699 was sulfated further highlighting the importance of FVIII sulfation at Y1699 for the binding affinity to vWF (Dagil L et al. 2019). The significance of the sulfation of FVIII at Y1699 in vivo is made evident by the presence of a Y1699F mutation that causes a moderate hemophilia A, likely due to reduced interaction with vWF and decreased plasma half-life (Higuchi M et al. 1990; van den Biggelaar M et al. 2011). The Reactome event describes defective O-sulfation of FVIII precursor due to mutation at Y1699. |
| (summation) | [FailedReaction:9668148] F8 variant is not sulfonated at Y1699 [Homo sapiens] |
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