Abstract
AbstractBinding to the von Willebrand factor (VWF) D′D3 domains protects factor VIII (FVIII) from rapid clearance. We performed single-particle electron microscopy (EM) analysis of negatively stained specimens to examine the architecture of D′D3 alone and in complex with FVIII. The D′D3 dimer ([D′D3]2) comprises 2 antiparallel D3 monomers with flexibly attached protrusions of D′. FVIII-VWF association is primarily established between the FVIII C1 domain and the VWF D′ domain, whereas weaker interactions appear to be mediated between both FVIII C domains and the VWF D3 core. Modeling the FVIII structure into the three-dimensional EM reconstructions of [D′D3]2-FVIII ternary and quaternary complexes indicates conformational rearrangements of the FVIII C domains compared with their disposition in the unbound state. These results illustrate the cooperative plasticity between VWF and FVIII that coordinate their high-affinity interaction.
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