Domain organization of membrane-bound factor VIII

Svetla Stoilova-Mcphie, Gillian C. Lynch, Steven Ludtke, Bernard Pettitt

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Factor VIII (FVIII) is the blood coagulation protein which when defective or deficient causes for hemophilia A, a severe hereditary bleeding disorder. Activated FVIII (FVIIIa) is the cofactor to the serine protease factor IXa (FIXa) within the membrane-bound Tenase complex, responsible for amplifying its proteolytic activity more than 100,000 times, necessary for normal clot formation. FVIII is composed of two noncovalently linked peptide chains: a light chain (LC) holding the membrane interaction sites and a heavy chain (HC) holding the main FIXa interaction sites. The interplay between the light and heavy chains (HCs) in the membrane-bound state is critical for the biological efficiency of FVIII. Here, we present our cryo-electron microscopy (EM) and structure analysis studies of human FVIII-LC, when helically assembled onto negatively charged single lipid bilayer nanotubes. The resolved FVIII-LC membrane-bound structure supports aspects of our previously proposed FVIII structure from membrane-bound two-dimensional (2D) crystals, such as only the C2 domain interacts directly with the membrane. The LC is oriented differently in the FVIII membrane-bound helical and 2D crystal structures based on EM data, and the existing X-ray structures. This flexibility of the FVIII-LC domain organization in different states is discussed in the light of the FVIIIa-FIXa complex assembly and function.

Original languageEnglish (US)
Pages (from-to)448-459
Number of pages12
JournalBiopolymers
Volume99
Issue number7
DOIs
StatePublished - Jul 2013

Fingerprint

Factor VIII
Membranes
Factor IXa
Light
cancer procoagulant
Electron microscopy
Factor VIIIa
Cryoelectron Microscopy
Nanotubes
Lipid bilayers
Hemophilia A
Biological Factors
Lipid Bilayers
Serine Proteases
Human engineering
Coagulation
Peptides
Blood Proteins
Electron Microscopy
Blood

Keywords

  • coagulation Factor VIII
  • cryo-electron microscopy
  • molecular modeling
  • protein-lipid interactions
  • structure determination

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Biomaterials
  • Organic Chemistry

Cite this

Stoilova-Mcphie, S., Lynch, G. C., Ludtke, S., & Pettitt, B. (2013). Domain organization of membrane-bound factor VIII. Biopolymers, 99(7), 448-459. https://doi.org/10.1002/bip.22199

Domain organization of membrane-bound factor VIII. / Stoilova-Mcphie, Svetla; Lynch, Gillian C.; Ludtke, Steven; Pettitt, Bernard.

In: Biopolymers, Vol. 99, No. 7, 07.2013, p. 448-459.

Research output: Contribution to journalArticle

Stoilova-Mcphie, S, Lynch, GC, Ludtke, S & Pettitt, B 2013, 'Domain organization of membrane-bound factor VIII', Biopolymers, vol. 99, no. 7, pp. 448-459. https://doi.org/10.1002/bip.22199
Stoilova-Mcphie, Svetla ; Lynch, Gillian C. ; Ludtke, Steven ; Pettitt, Bernard. / Domain organization of membrane-bound factor VIII. In: Biopolymers. 2013 ; Vol. 99, No. 7. pp. 448-459.
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