Mechano‐covalent protection 1 of procoagulant factor VIII by von Willebrand factor

ABSTRACT: von Willebrand factor (VWF) is the protective carrier of procoagulant factor VIII (FVIII) in the shear forces of the circulation, prolonging its half‐life and delivering it to the developing thrombus. VWF∙FVIII complex formation is characterized by catch‐bond behavior in which force first decelerates then accelerates bond dissociation. Patients with mutations in VWF at the FVIII binding site phenocopies hemophilia A and the most common mutations involve cysteine residues of multiple disulfides. Thirteen VWF disulfide bonds at the FVIII binding site exist in formed and unformed states, and binding of FVIII results in partial formation of 12 of the VWF bonds. The VWF∙FVIII bond stiffens in response to force and this property is ablated when VWF disulfide bonds are prevented from forming, resulting in slip‐bond behavior. These findings demonstrate that FVIII binding to VWF involves dynamic changes in the covalent states of several VWF disulfides that are required for productive interaction.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Plasma

SUBMITTER: Diego Butera  

LAB HEAD: Philip John Hogg

PROVIDER: PXD034866 | Pride | 2023-07-20

REPOSITORIES: Pride