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 journalArticlepeer-review

13 Scopus citations


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
StatePublished - Jun 17 2015
Externally publishedYes

ASJC Scopus subject areas

  • General


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