title: Visualization of an N-terminal fragment of von Willebrand factor in complex with factor VIII.
abstract: 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.
authors.affiliation: Life Sciences Institute.
authors.forename: Andrew
authors.identifier: http://orcid.org/0000-0003-0304-6322
authors.initials: A
authors.lastname: Yee
authors.affiliation: Life Sciences Institute.
authors.forename: Austin N
authors.initials: AN
authors.lastname: Oleskie
authors.affiliation: Life Sciences Institute.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Dosey
authors.affiliation: Life Sciences Institute.
authors.forename: Colin A
authors.initials: CA
authors.lastname: Kretz
authors.affiliation: Life Sciences Institute.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Gildersleeve
authors.affiliation: Life Sciences Institute.
authors.forename: Somnath
authors.initials: S
authors.lastname: Dutta
authors.affiliation: Life Sciences Institute.
authors.forename: Min
authors.initials: M
authors.lastname: Su
authors.affiliation: Life Sciences Institute, Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI; Departments of Internal Medicine, Human Genetics, and Pediatrics and Communicable Diseases, and.
authors.forename: David
authors.identifier: http://orcid.org/0000-0002-6436-8942
authors.initials: D
authors.lastname: Ginsburg
authors.affiliation: Life Sciences Institute, Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI.
authors.forename: Georgios
authors.initials: G
authors.lastname: Skiniotis
mesh_terms: D005169:Factor VIII / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008854:Microscopy, Electron; D008958:Models, Molecular; D010446:Peptide Fragments; D020836:Protein Structure, Quaternary; D014841:von Willebrand Factor / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D010446:Peptide Fragments; D014841:von Willebrand Factor; D005169:Factor VIII