Visualization of an N-terminal fragment of von Willebrand factor in complex with factor VIII
Binding 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) comp...
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Published in | Blood Vol. 126; no. 8; pp. 939 - 942 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Elsevier Inc
20.08.2015
American Society of Hematology |
Series | Thrombosis and Hemostasis |
Subjects | |
Online Access | Get full text |
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Summary: | Binding 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.
•The VWF D′ domains are flexibly tethered entities projecting outside antiparallel dimers of the VWF D3 domain.•Extensive interactions between the VWF D′ domain and primarily the FVIII C1 domain mediate VWF-FVIII association. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0006-4971 1528-0020 |
DOI: | 10.1182/blood-2015-04-641696 |