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.

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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.