National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)
1F30HL162128
米国
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)
R01-HL148755
米国
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
R01-GM141109
米国
引用
ジャーナル: Blood / 年: 2022 タイトル: Structures of VWF tubules before and after concatemerization reveal a mechanism of disulfide bond exchange. 著者: Jacob R Anderson / Jing Li / Timothy A Springer / Alan Brown / 要旨: von Willebrand factor (VWF) is an adhesive glycoprotein that circulates in the blood as disulfide-linked concatemers and functions in primary hemostasis. The loss of long VWF concatemers is ...von Willebrand factor (VWF) is an adhesive glycoprotein that circulates in the blood as disulfide-linked concatemers and functions in primary hemostasis. The loss of long VWF concatemers is associated with the excessive bleeding of type 2A von Willebrand disease (VWD). Formation of the disulfide bonds that concatemerize VWF requires VWF to self-associate into helical tubules, yet how the helical tubules template intermolecular disulfide bonds is not known. Here, we report electron cryomicroscopy (cryo-EM) structures of VWF tubules before and after intermolecular disulfide bond formation. The structures provide evidence that VWF tubulates through a charge-neutralization mechanism and that the A1 domain enhances tubule length by crosslinking successive helical turns. In addition, the structures reveal disulfide states before and after disulfide bond-mediated concatemerization. The structures and proposed assembly mechanism provide a foundation to rationalize VWD-causing mutations.