Shen Betty W, Spiegel Paul Clint, Chang Chong-Hwan, Huh Jae-Wook, Lee Jung-Sik, Kim Jeanman, Kim Young-Ho, Stoddard Barry L
Program in Molecular Biophysics, Structure and Design, Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Blood. 2008 Feb 1;111(3):1240-7. doi: 10.1182/blood-2007-08-109918. Epub 2007 Oct 26.
Factor VIII (fVIII) is a serum protein in the coagulation cascade that nucleates the assembly of a membrane-bound protease complex on the surface of activated platelets at the site of a vascular injury. Hemophilia A is caused by a variety of mutations in the factor VIII gene and typically requires replacement therapy with purified protein. We have determined the structure of a fully active, recombinant form of factor VIII (r-fVIII), which consists of a heterodimer of peptides, respectively containing the A1-A2 and A3-C1-C2 domains. The structure permits unambiguous modeling of the relative orientations of the 5 domains of r-fVIII. Comparison of the structures of fVIII, fV, and ceruloplasmin indicates that the location of bound metal ions and of glycosylation, both of which are critical for domain stabilization and association, overlap at some positions but have diverged at others.
凝血因子VIII（fVIII）是凝血级联反应中的一种血清蛋白，在血管损伤部位的活化血小板表面，它能促使膜结合蛋白酶复合物的组装。甲型血友病是由凝血因子VIII基因的多种突变引起的，通常需要用纯化蛋白进行替代治疗。我们已经确定了一种完全活性的重组凝血因子VIII（r-fVIII）的结构，它由肽的异二聚体组成，分别包含A1-A2和A3-C1-C2结构域。该结构允许对r-fVIII的5个结构域的相对取向进行明确建模。fVIII、fV和铜蓝蛋白结构的比较表明，结合金属离子和糖基化的位置，这两者对结构域的稳定和结合都至关重要，在某些位置重叠，但在其他位置有所不同。
