BLOOD COAGULATION FACTOR

Baylor College Of Medicine, Houston TX

Investigators

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Blood coagulation is ensured through equilibrium between pro- and anti-coagulant coagulation factors that interact with each other and cells. Factor VIII (FVIII) is a large multidomain protein (~280kDa), which in its active form, Factor VIIIa (FVIIIa) acts as a co-factor to the serine protease Factor IXa (FIXa) within the membrane-bound Tenase complex. Binding of FVIIIa to FIXa onto the platelet surface increases Factor Xa (FXa) and Thrombin generation more than 10^6 times. Mutations in FVIII result in mild to severe Haemophilia type A, a life-threatening blood condition affecting one in 5000 of the male population (Wacey et al., 1996). The sole cure for this condition is intravenous administration of FVIII, whose membrane-bound structure has been studied by Stoilova-McPhie using electron microscopy (Parmenter and Stoilova-McPhie, 2008;Stoilova-McPhie et al., 2008). CryoEM is a unique method capable of defining the structure of proteins in their native environment. For this purpose we have designed lipid nanotubes (LNT) for helical crystallization of FVIII and its complexes, allowing its membrane-bond structure to be resolved by Cryo-EM. Defining the structure of membrane-bound blood coagulation Factor Va and Factor VIIIa attached to lipid nanotubes by Cryo-electron microscopy is the primary goal of this project.