Chapter Ten Role of von Willebrand Factor—A1 Domain Variants P1266L, H1268D, C1272R, and C1272F in VWD

Publication date: 2016 Source:Advances in Protein Chemistry and Structural Biology, Volume 102 Author(s): C. George Priya Doss, Shabana Kouser Ali von Willebrand disease (VWD) is an autosomal inherited disorder related to trauma-related bleeding in affected people. VWD results from deficiency of von Willebrand factor (VWF)—a glycoprotein involved in hemostasis and carrier for factor VIII (FVIII). Mutations in A1 domain of von Willebrand factor (VWD) gene are exceptionally polymorphic and associated with adhesion movement, clearance, and binding properties that could be interfaced with thrombosis. To address this issue, we implemented in silico prediction algorithms, namely, SIFT, PolyPhen 2.0, I-Mutant 3.0, SNAP, Align GVGD, PhD-SNP, SNPs&GO, and MutPred to classify the variants as pathogenic and affecting protein stability. Based on prediction scores, four variants, namely, P1266L, H1268D, C1272R, and C1272F, were predicted as highly deleterious from a pool of 72 nsSNPs/variants in A1 domain of VWD belonging to type 2A and 2B. Upon literature survey, amino acid substitution (P→L) at position 1266 is involved in improving the connection with platelets, substitution (C→F) at position 1272 results in extreme bleeding in patients, and substitution (H→D) at position 1268 disturbs the salt bridge scaffold were considered for further analysis. Through molecular dynamic simulation analysis over a period of 100ns showed that four mutations near N-terminal regi...
Source: Advances in Protein Chemistry and Structural Biology - Category: Biochemistry Source Type: research