THE SOLUTION STRUCTURE OF HUMAN COAGULATION-FACTOR VIIA IN ITS COMPLEX WITH TISSUE FACTOR IS SIMILAR TO FREE FACTOR VIIA - A STUDY OF A HETERODIMERIC RECEPTOR-LIGAND COMPLEX BY X-RAY AND NEUTRON-SCATTERING ANDCOMPUTATIONAL MODELING

Factor VIIa (FVIIa) is a soluble four-domain plasma serine protease co agulation factor that forms a tight complex with the two extracellular domains of the transmembrane protein tissue factor in the initiating step of blood coagulation. To date, there is no crystal structure for free FVIIa. X-ray and neutron scattering data in solution for free FVI Ia and the complex between FVIIa and soluble tissue factor (sTF) had b een obtained for comparison with crystal structures of the FVIIa-sTF c omplex and of free factor IXa (FIXa). The solution structure of free F VIIa as derived from scattering data is consistent with the extended d omain arrangement of FVIIa seen in the crystal structure of its comple x with sTF, but is incompatible with the bent, less extended domain co nformation seen in the FIXa crystal structure. The FVIIa scattering cu rve is also compatible with a subset of 317 possible extended structur es derived from a constrained automated conformational search of 15 62 5 FVIIa domain models. Thus, the scattering data support extended doma in models for FVIIa free in solution. Similar analyses showed that the solution scattering derived and crystal structures of the FVIIa-sTF c omplex were in good agreement. An automated constrained search for all owed structures for the complex in solution based on scattering curves showed that only a small family of compact models gave good agreement , namely these in which FVIIa and sTF interact closely over a large su rface area. The general utility of this approach for structural analys is of heterodimeric complexes in solution is discussed. Analytical ult racentrifugation data and the modeling of these data were consistent w ith the scattering results. It is concluded that in solution FVIIa has an extended or elongated domain structure, which allows rapid interac tion with sTF over a large surface area to form a high-affinity comple x.