Dimeric organization of blood coagulation factor VIII bound to lipid nanotubes

Daniela Dalm, Jesus G. Galaz-Montoya, Jaimy L. Miller, Kirill Grushin, Alex Villalobos, Alexey Y. Koyfman, Michael F. Schmid, Svetla Stoilova-McPhie

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Membrane-bound Factor VIII (FVIII) has a critical function in blood coagulation as the pro-cofactor to the serine-protease Factor IXa (FIXa) in the FVIIIa-FIXa complex assembled on the activated platelet membrane. Defects or deficiency of FVIII cause Hemophilia A, a mild to severe bleeding disorder. Despite existing crystal structures for FVIII, its membrane-bound organization has not been resolved. Here we present the dimeric FVIII membrane-bound structure when bound to lipid nanotubes, as determined by cryo-electron microscopy. By combining the structural information obtained from helical reconstruction and single particle subtomogram averaging at intermediate resolution (15-20 Å), we show unambiguously that FVIII forms dimers on lipid nanotubes. We also demonstrate that the organization of the FVIII membrane-bound domains is consistently different from the crystal structure in solution. The presented results are a critical step towards understanding the mechanism of the FVIIIa-FIXa complex assembly on the activated platelet surface in the propagation phase of blood coagulation.

Original languageEnglish (US)
Article number11212
JournalScientific Reports
Volume5
DOIs
StatePublished - Jun 17 2015

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Nanotubes
Factor VIII
Factor IXa
Lipids
Membranes
Hemophilia A
Blood Coagulation
Blood Platelets
Cryoelectron Microscopy
Serine Proteases
Hemorrhage

ASJC Scopus subject areas

  • General

Cite this

Dalm, D., Galaz-Montoya, J. G., Miller, J. L., Grushin, K., Villalobos, A., Koyfman, A. Y., ... Stoilova-McPhie, S. (2015). Dimeric organization of blood coagulation factor VIII bound to lipid nanotubes. Scientific Reports, 5, [11212]. https://doi.org/10.1038/srep11212

Dimeric organization of blood coagulation factor VIII bound to lipid nanotubes. / Dalm, Daniela; Galaz-Montoya, Jesus G.; Miller, Jaimy L.; Grushin, Kirill; Villalobos, Alex; Koyfman, Alexey Y.; Schmid, Michael F.; Stoilova-McPhie, Svetla.

In: Scientific Reports, Vol. 5, 11212, 17.06.2015.

Research output: Contribution to journalArticle

Dalm, D, Galaz-Montoya, JG, Miller, JL, Grushin, K, Villalobos, A, Koyfman, AY, Schmid, MF & Stoilova-McPhie, S 2015, 'Dimeric organization of blood coagulation factor VIII bound to lipid nanotubes', Scientific Reports, vol. 5, 11212. https://doi.org/10.1038/srep11212
Dalm D, Galaz-Montoya JG, Miller JL, Grushin K, Villalobos A, Koyfman AY et al. Dimeric organization of blood coagulation factor VIII bound to lipid nanotubes. Scientific Reports. 2015 Jun 17;5. 11212. https://doi.org/10.1038/srep11212
Dalm, Daniela ; Galaz-Montoya, Jesus G. ; Miller, Jaimy L. ; Grushin, Kirill ; Villalobos, Alex ; Koyfman, Alexey Y. ; Schmid, Michael F. ; Stoilova-McPhie, Svetla. / Dimeric organization of blood coagulation factor VIII bound to lipid nanotubes. In: Scientific Reports. 2015 ; Vol. 5.
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