The tertiary structure and domain organization of coagulation factor VIII
The tertiary structure and domain organization of coagulation factor VIII
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DOI：
10.1182/blood-2007-08-109918
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发表时间：
2008-02-01
期刊：
影响因子：
20.3
通讯作者：
Stoddard, Barry L.
中科院分区：
文献类型：
--
作者：
Shen, Betty W.;Spiegel, Paul Clint;Stoddard, Barry L.
因子VIII（fVIII）是凝血级联中的一种血清蛋白，其使血管损伤部位处的活化血小板表面上的膜结合蛋白酶复合物的组装成核。血友病A是由因子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形式的因子VIII（r-fVIII）的结构，它由肽的异源二聚体组成，分别含有A1-A2和A3-C1-C2结构域。该结构允许对r-fVIII的5个结构域的相对方向进行明确建模。FVIII，FV和血浆铜蓝蛋白的结构的比较表明，结合的金属离子和糖基化的位置，这两者都是结构域的稳定和关联的关键，在某些位置重叠，但在其他人有分歧。
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.