Poster Title

Structural Studies of Blood Coagulation Factor VIII in Complexes in Circulation

Research Mentor(s)

Clint Spiegel

Affiliated Department

Chemistry

Sort Order

43

Start Date

14-5-2015 10:00 AM

End Date

14-5-2015 2:00 PM

Document Type

Event

Abstract

Hemophilia A is a bleeding disorder caused by the loss of factor VIII (fVIII) function. When vascular injury occurs, this plasma glycoprotein functions as a cofactor for the serine protease factor IXa and facilitates blood coagulation by nucleating the assembly of a membrane-bound protease complex on the surface of activated platelets. This complex proteolytically activates fX to fXa, which subsequently converts prothrombin to thrombin, ultimately aiding in the formation of a fibrin clot. Common and effective treatment for hemophilia A is replacement therapy with either plasma-derived or recombinant fVIII. These fVIII products are effective, but limited by price and availability. Recently, a hybrid human-porcine fVIII was developed using a novel lentiviral-driven recombinant protein manufacturing platform, resulting in 16- to 160-fold greater yield of therapeutic protein. This could contribute to the production of future clinical hemophilia A therapeutics and facilitate the treatment of a larger proportion of patients with hemophilia A. For structural studies of the engineered fVIII, protein crystallography was utilized. A promising approach in protein crystallization is to select a high affinity binding partner, such as an antibody to fVIII. Following complex formation, crystallization trials have been performed. A binding partner (the antibody) can potentially reduce the conformational freedom of fVIII and additionally aid in the formation of well-ordered crystals for improved X-ray diffraction.

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

This document is currently not available here.

Share

COinS
 
May 14th, 10:00 AM May 14th, 2:00 PM

Structural Studies of Blood Coagulation Factor VIII in Complexes in Circulation

Chemistry

Hemophilia A is a bleeding disorder caused by the loss of factor VIII (fVIII) function. When vascular injury occurs, this plasma glycoprotein functions as a cofactor for the serine protease factor IXa and facilitates blood coagulation by nucleating the assembly of a membrane-bound protease complex on the surface of activated platelets. This complex proteolytically activates fX to fXa, which subsequently converts prothrombin to thrombin, ultimately aiding in the formation of a fibrin clot. Common and effective treatment for hemophilia A is replacement therapy with either plasma-derived or recombinant fVIII. These fVIII products are effective, but limited by price and availability. Recently, a hybrid human-porcine fVIII was developed using a novel lentiviral-driven recombinant protein manufacturing platform, resulting in 16- to 160-fold greater yield of therapeutic protein. This could contribute to the production of future clinical hemophilia A therapeutics and facilitate the treatment of a larger proportion of patients with hemophilia A. For structural studies of the engineered fVIII, protein crystallography was utilized. A promising approach in protein crystallization is to select a high affinity binding partner, such as an antibody to fVIII. Following complex formation, crystallization trials have been performed. A binding partner (the antibody) can potentially reduce the conformational freedom of fVIII and additionally aid in the formation of well-ordered crystals for improved X-ray diffraction.