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Date Permissions Signed
Date of Award
Department or Program Affiliation
Department of Chemistry
Master of Science (MS)
Spiegel, P. Clint
Smirnov, Sergey L.
Hemophilia A is an X-linked disorder that results in uncontrolled bleeding, which is caused by a lack of activity for blood coagulation factor VIII, an essential protein cofactor in the clotting cascade. Factor VIII consists of multiple domains, and binding disruptions between factor VIII and its circulatory partner, von Willebrand Factor, may cause von Willebrand disease. Von Willebrand Disease type 2N is an autosomal recessive disease, and it is caused by binding disruptions between the D’ domain (also known as TIL’E’) of von Willebrand Factor and a3 domain of factor VIII. A 2.9Å Cryoelectron microscopy structure of the FVIII:vWF complex was recently published, and this crystal structure further described the interactions between FVIII and vWF. To further understand the most severe types of von Willebrand Disease type 2N, site-directed mutagenesis of vWF was employed to enhance the understanding of binding disruptions between vWF and FVIII. The designed mutants were transformed, expressed, and purified for further experimental studies. Binding assays were conducted between the mutants against our bioengineered chimeric structure factor VIII, ET3i, via pull-down assays, sedimentation assays, as well as quantitative studies via biolayer interferometry. The results of this present study included the investigation of binding studies between the D’ domain of von Willebrand factor and the a3 domain of factor VIII. The results obtained in this study were interpreted, compared, and concluded to be consistent with the newest cryo-EM structure.
Factor VIII, von Willebrand Factor, FVIII, vWF, vWD, hemophilia A
Western Washington University
Subject – LCSH
Von Willebrand factor; Von Willebrand disease; Hemophilia; Blood coagulation factor VIII
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Wang, AP, "Structural Studies of the von Willebrand Factor D’ domain and its Binding Mechanism to Factor VIII" (2021). WWU Graduate School Collection. 1050.