zEvidence for the Misfolding of the A1 Domain within Multimeric von Willebrand Factor in Type 2 von Willebrand Disease

Publication date: Available online 17 October 2019Source: Journal of Molecular BiologyAuthor(s): Alexander Tischer, Maria A. Brehm, Venkata R. Machha, Laurie Moon-Tasson, Linda M. Benson, Katelynn J. Nelton, Rachel R. Leger, Tobias Obser, Marina Martinez-Vargas, Steven T. Whitten, Dong Chen, Rajiv K. Pruthi, H. Robert Bergen, Miguel A. Cruz, Reinhard Schneppenheim, Matthew AutonAbstractVon Willebrand factor (VWF), an exceptionally large multimeric plasma glycoprotein, functions to initiate coagulation by agglutinating platelets in the blood stream to sites of vascular injury. This primary hemostatic function is perturbed in type 2 dysfunctional subtypes of von Willebrand disease (VWD) by mutations that alter the structure and function of the platelet GPIbα adhesive VWF A1 domains. The resulting amino acid substitutions cause local disorder and misfolding of the native structure of the isolated platelet GPIbα adhesive A1 domain of VWF in both gain-of-function (type 2B) and loss-of-function (type 2M) phenotypes. These structural effects have not been explicitly observed in A1 domains of VWF multimers native to blood plasma. New mass spectrometry strategies are applied to resolve the structural effects of 2B and 2M mutations in VWF to verify the presence of A1 domain structural disorder in multimeric VWF harboring type 2 VWD mutations. Limited trypsinolysis (LTMS) and hydrogen deuterium exchange (HXMS) are applied to wild type and VWD variants of the single A1, A2 and A3-domai...
Source: Journal of Molecular Biology - Category: Molecular Biology Source Type: research