The 1.7 Å X-ray crystal structure of the porcine factor VIII C2 domain and binding analysis to anti-human C2 domain antibodies and phospholipid surfaces

PloS One
Caileen M BrisonP C Spiegel

Abstract

The factor VIII C2 domain is essential for binding to activated platelet surfaces as well as the cofactor activity of factor VIII in blood coagulation. Inhibitory antibodies against the C2 domain commonly develop following factor VIII replacement therapy for hemophilia A patients, or they may spontaneously arise in cases of acquired hemophilia. Porcine factor VIII is an effective therapeutic for hemophilia patients with inhibitor due to its low cross-reactivity; however, the molecular basis for this behavior is poorly understood. In this study, the X-ray crystal structure of the porcine factor VIII C2 domain was determined, and superposition of the human and porcine C2 domains demonstrates that most surface-exposed differences cluster on the face harboring the "non-classical" antibody epitopes. Furthermore, antibody-binding results illustrate that the "classical" 3E6 antibody can bind both the human and porcine C2 domains, although the inhibitory titer to human factor VIII is 41 Bethesda Units (BU)/mg IgG versus 0.8 BU/mg IgG to porcine factor VIII, while the non-classical G99 antibody does not bind to the porcine C2 domain nor inhibit porcine factor VIII activity. Further structural analysis of differences between the electros...Continue Reading

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Citations

Nov 26, 2015·Scientific Reports·Michelle E WuerthP Clint Spiegel
Aug 28, 2019·Journal of Thrombosis and Haemostasis : JTH·Ian W SmithPaul Clint Spiegel

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Methods Mentioned

BETA
X-ray
size exclusion chromatography
ELISA

Software Mentioned

CrystalClear
PHENIX
HKL2000
Molprobity
PyMol
COOT
GraphPad Prism
APBS
PHASER

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