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TitleDimeric Organization of Blood Coagulation Factor VIII bound to Lipid Nanotubes.
Journal, issue, pagesSci Rep, Vol. 5, Page 11212, Year 2015
Publish dateJun 17, 2015
AuthorsDaniela Dalm / Jesus G Galaz-Montoya / Jaimy L Miller / Kirill Grushin / Alex Villalobos / Alexey Y Koyfman / Michael F Schmid / Svetla Stoilova-McPhie /
PubMed AbstractMembrane-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 ...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.
External linksSci Rep / PubMed:26082135 / PubMed Central
MethodsEM (subtomogram averaging) / EM (helical sym.)
Resolution15.5 - 21.0 Å
Structure data

EMDB-3026:
Electron cryo-microscopy of porcine Factor VIII bound to lipid nanotubes and single particle tomography reconstruction
Method: EM (subtomogram averaging) / Resolution: 21.0 Å

EMDB-3027:
Electron cryo-microscopy of porcine Factor VIII bound to lipid nanotubes and helical reconstruction
Method: EM (helical sym.) / Resolution: 15.5 Å

Source
  • Sus scrofa (pig)
  • unidentified (others)

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