Document Type

Article

Publication Date

11-24-2015

Keywords

Hemophilia A, Blood coagulation factor VIII, Factor VIII, Coagulation system, X-ray crystallography

Abstract

Blood coagulation factor VIII is a glycoprotein cofactor that is essential for the intrinsic pathway of the blood coagulation cascade. Inhibitory antibodies arise either spontaneously or in response to therapeutic infusion of functional factor VIII into hemophilia A patients, many of which are specific to the factor VIII C2 domain. The immune response is largely parsed into “classical” and “non-classical” inhibitory antibodies, which bind to opposing faces cooperatively. In this study, the 2.61Å resolution structure of the C2 domain in complex with the antigen-binding fragment of the 3E6 classical inhibitory antibody is reported. The binding interface is largely conserved when aligned with the previously determined structure of the C2 domain in complex with two antibodies simultaneously. Further inspection of the B factors for the C2 domain in various X-ray crystal structures indicates that 3E6 antibody binding decreases the thermal motion behavior of surface loops in the C2 domain on the opposing face, thereby suggesting that cooperative antibody binding is a dynamic effect. Understanding the structural nature of the immune response to factor VIII following hemophilia A treatment will help lead to the development of better therapeutic reagents.

Publication Title

Scientific Reports

Volume

5

Issue

1

First Page

17216

Genre/Form

articles

Required Publisher's Statement

Published by Springer Nature

Subjects - Topical (LCSH)

Blood coagulation factor VIII; Blood coagulation factor VIII antibodies; Blood coagulation factors; Hemophilia; Coagulants

spiegel supp file srep17216-s1.pdf (195 kB)
Supplemental file

Type

Text

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

Language

English

Format

application/pdf

Included in

Chemistry Commons

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