Structural Studies of Blood Coagulation Factor VIII in Protein Complexes
Research Mentor(s)
Spiegel, P. Clint
Description
A deficiency in blood coagulation factor VIII (fVIII) is responsible for the inherited bleeding disorder hemophilia A, which affects approximately 1 in 5000 males. The development of inhibitory antibodies is a significant issue faced by hemophilia A patients receiving therapeutic infusions of fVIII. The C-terminal C2 domain of fVIII has been shown to be highly immunogenic and the site of binding for numerous antibodies of both the classical and non-classical classifications. A detailed understanding of the structural components involved in C2-antibody binding interactions is vital for the development of improved therapeutics for hemophilia patients. Here we present the structure of the classical antibody 3E6 bound to human C2 at 2.6 Å resolution. Previous studies have suggested that pairs of classical and non-classical antibodies may exhibit binding cooperativity. We hope to elucidate the molecular basis for this cooperativity through analysis of the structure of C2-3E6 and a previously determined ternary structure of C2 bound simultaneously to both 3E6 and the non-classical antibody G99. Furthermore, we are currently employing crystallographic techniques to study the interactions between FVIII and its circulatory partner von Willebrand factor (vWF), which is crucial for maintaining FVII levels in plasma. Two vWF domain mutants, TIL'E' and D'D3, are being studied in complex with FVIII to elucidate detailed binding information.
Document Type
Event
Start Date
14-5-2015 10:00 AM
End Date
14-5-2015 2:00 PM
Department
Chemistry
Genre/Form
student projects; posters
Subjects – Topical (LCSH)
Blood coagulation factor VIII; Blood proteins--Structure; Hemophilia--Treatment
Type
Image
Rights
Copying of this document in whole or in part is allowable only for scholarly purposes. It is understood, however, that any copying or publication of this documentation for commercial purposes, or for financial gain, shall not be allowed without the author's written permission.
Language
English
Format
application/pdf
Structural Studies of Blood Coagulation Factor VIII in Protein Complexes
A deficiency in blood coagulation factor VIII (fVIII) is responsible for the inherited bleeding disorder hemophilia A, which affects approximately 1 in 5000 males. The development of inhibitory antibodies is a significant issue faced by hemophilia A patients receiving therapeutic infusions of fVIII. The C-terminal C2 domain of fVIII has been shown to be highly immunogenic and the site of binding for numerous antibodies of both the classical and non-classical classifications. A detailed understanding of the structural components involved in C2-antibody binding interactions is vital for the development of improved therapeutics for hemophilia patients. Here we present the structure of the classical antibody 3E6 bound to human C2 at 2.6 Å resolution. Previous studies have suggested that pairs of classical and non-classical antibodies may exhibit binding cooperativity. We hope to elucidate the molecular basis for this cooperativity through analysis of the structure of C2-3E6 and a previously determined ternary structure of C2 bound simultaneously to both 3E6 and the non-classical antibody G99. Furthermore, we are currently employing crystallographic techniques to study the interactions between FVIII and its circulatory partner von Willebrand factor (vWF), which is crucial for maintaining FVII levels in plasma. Two vWF domain mutants, TIL'E' and D'D3, are being studied in complex with FVIII to elucidate detailed binding information.