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TitleStructures of VWF tubules before and after concatemerization reveal a mechanism of disulfide bond exchange.
Journal, issue, pagesBlood, Vol. 140, Issue 12, Page 1419-1430, Year 2022
Publish dateSep 22, 2022
AuthorsJacob R Anderson / Jing Li / Timothy A Springer / Alan Brown /
PubMed Abstractvon 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.
External linksBlood / PubMed:35776905 / PubMed Central
MethodsEM (helical sym.)
Resolution3.1 - 4.7 Å
Structure data

EMDB-27156, PDB-8d3c:
VWF tubule derived from monomeric D1-A1
Method: EM (helical sym.) / Resolution: 3.1 Å

EMDB-27157, PDB-8d3d:
VWF tubule derived from dimeric D1-A1
Method: EM (helical sym.) / Resolution: 3.2 Å

EMDB-27158: VWF tubule derived from dimeric D1-A2
Method: EM (helical sym.) / Resolution: 4.7 Å

Chemicals

ChemComp-CA:
Unknown entry

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

Source
  • homo sapiens (human)
KeywordsBLOOD CLOTTING / VWF / tubule

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