Factor VIII and von Willebrand Factor
Factor VIII and von Willebrand Factor
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因子 VIII 和血管性血友病因子
DOI：
10.1055/s-0037-1614927
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发表时间：
1998
影响因子：
6.7
通讯作者：
J. Sixma
中科院分区：
文献类型：
--
作者：
A. Vlot;Stefan Koppelman;B. Bouma;J. Sixma
因子VIII和血管性血友病因子是血浆糖蛋白，其缺乏或结构缺陷分别导致血友病A和血管性血友病（1）。这些疾病是人类最常见的遗传性出血性疾病。因子VIII和vWF由不同类型的细胞合成，并作为紧密结合的复合物在血浆中循环。因子VIII在肝脏中合成（2），并在膜表面上因子X的内在活化中作为活化因子IX的辅因子发挥作用（3）。vWF在内皮细胞（4，5）和巨核细胞（6）中合成。vWF在止血中具有双重作用：在血管损伤后促进血小板粘附于内皮下（7，8），并作为因子VIII的载体蛋白（1）。因子VIII和vWF之间的区别多年来一直不清楚，因为严重的血管性血友病与因子VIII缺乏有关，并且因为早期制备的因子VIII浓缩物含有vWF，因此可有效纠正血管性血友病患者的血小板粘附缺陷（9）。由于因子VIII和vWF在血浆中形成紧密结合的非共价复合物，因此除非采取特殊措施，否则从血浆中分离时，两种蛋白质均为共纯化蛋白（1）。血浆中因子VIII和vWF的化学计量约为1：50，因子VIII和单体vWF具有相似的分子量，约为240 kDa。因此，vWF占因子VIII-vWF复合物分子量的98%（10），几乎所有针对复合物的抗体都与vWF反应。在20世纪80年代，因子VIII和vWF各自被纯化至同质，并且这些蛋白质的基因已经被克隆。这为纯化蛋白质的研究奠定了基础，这些蛋白质已经阐明了两种蛋白质的结构-功能关系。此外，可以使用蛋白水解片段、小肽和单克隆抗体来研究这两种蛋白质之间的相互作用。在过去的几年中，因子VIII（11-13）和vWF（14-16）的重组突变体和片段的构建已被证明是阐明这两种蛋白质的结构和功能的有力工具。因子VIII与vWF的结合对于因子VIII在体内的存活至关重要（17，18）。潜在机制可能是活化蛋白C和因子Xa保护与vWF结合的因子VIII免受磷脂依赖性蛋白水解（19，20）。因子VIII的结合位点位于vWF的氨基末端（21，22）。根据某些研究组的研究，含有该结合位点的胰蛋白酶片段不足以保护因子VIII免受活化蛋白C介导的降解（23，24）。相比之下，最近一项使用可比较vWF片段的研究显示，因子VIII的保护作用与成熟vWF相当（16）。1989年，发现了一种新的von Willebrand病变体（诺曼底型或2N型），与已知的20多种亚型不同，其特征在于突变型vWF，其结构和功能正常，但不结合并稳定因子VIII（25，26）。从那时起，在vWF上的因子VIII结合位点中发现了几个突变（27）。许多报道显示因子VIII通过其轻链上的高亲和力结合位点结合vWF（28-30）。最近的两项研究表明，该结合位点由两个独立的结合位点组成（31，32）。本文综述了目前的知识之间的相互作用因子VIII和vWF。重点将放在结合的生物学重要性和涉及的领域，以及复合物形成的化学计量和动力学上。
Introducation Factor VIII and von Willebrand factor are plasma glycoproteins whose deficiency or structural defects cause hemophilia A and von Willebrand disease, respectively (1). These diseases are the most common inherited bleeding disorders of man. Factor VIII and vWF are synthesized by different cell types and circulate in plasma as a tightly bound complex. Factor VIII is synthesized in the liver (2), and functions as a cofactor for activated factor IX in the intrinsic activation of factor X on a membrane surface (3). vWF is synthesized in endothelial cells (4, 5) and megakaryocytes (6). vWF has a dual role in hemostasis: it promotes platelet adhesion to subendothelium after vessel injury (7, 8) and it acts as a carrier protein of factor VIII (1). The distinction between factor VIII and vWF was unclear for many years, because severe Von Willebrand disease is associated with factor VIII deficiency and because early preparations of factor VIII concentrates contained vWF and were therefore effective in correcting the platelet adhesion defects in patients with von Willebrand disease (9). Since factor VIII and vWF form a tightly bound non-covalent complex in plasma, both proteins are copurified when isolated from plasma, unless special measures are taken (1). The stoichiometry of factor VIII and vWF in plasma is approximately 1:50 and factor VIII and monomeric vWF have similar molecular weights of approximately 240 kDa. Therefore, vWF represents 98% of the molecular mass of the factor VIII-vWF complex (10) and almost all the antibodies raised against the complex react to vWF. In the 1980’s, factor VIII and vWF have each been purified to homogeneity and the genes for these proteins have been cloned. This set the stage for studies with purified proteins which have elucidated structure-function relationships for both proteins. Also, the interaction between both proteins could be studied using proteolytic fragments, small peptides, and monoclonal antibodies. In the last few years, the construction of recombinant mutants and fragments of both factor VIII (11-13) and vWF (14-16) has proven to be a powerful tool in the elucidation of the structure and function of both proteins. Binding of factor VIII to vWF is essential for the survival of factor VIII in vivo (17, 18). The underlying mechanism is probably that factor VIII bound to vWF is protected from phospholipid dependent proteolysis by activated protein C and factor Xa (19, 20). The binding site for factor VIII has been located at the amino terminus of vWF (21, 22). A tryptic fragment containing this binding site was not sufficient to protect factor VIII against activated protein C-mediated degradation according to some groups (23, 24). In contrast, a recent study using comparable vWF fragments showed protection of factor VIII equivalent to mature vWF (16). In 1989, a new variant of von Willebrand disease was discerned (type Normandy or 2N), distinct from the more than 20 subtypes known, characterized by a mutant vWF that is structurally and functionally normal, except that it does not bind to and stabilize factor VIII (25, 26). Since then, several mutations in the factor VIII binding site on vWF have been found (27). A number of reports have shown that factor VIII binds vWF via a high affinity binding site on its light chain (28-30). Two recent studies suggest that this binding site consists of two separate binding sites (31, 32). This review summarizes current knowledge on the interaction between factor VIII and vWF. Emphasis will be laid on the biological importance of, and the domains involved in binding, and on the stoichiometry and kinetics of complex formation.
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低纯度和中纯度凝血因子治疗对先天性凝血障碍中人类免疫缺陷病毒感染进展的影响。
影响因子：
20.3
作者：
Gjerset,GF;Pike,MC;Mosley,JW;Hassett,J;Fletcher,MA;Donegan,E;Parker,JW;Counts,RB;Zhou,Y;Kasper,CK
通讯作者：
Kasper,CK
影响因子：
2.9
作者：
DAVIE, EW;FUJIKAWA, K;KISIEL, W
通讯作者：
KISIEL, W
主要因子 VIII 结合域位于冯·维勒布兰德因子的氨基末端 272 个氨基酸残基内。
DOI：
--
发表时间：
1987
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Foster,PA;Fulcher,CA;Marti,T;Titani,K;Zimmerman,TS
通讯作者：
Zimmerman,TS
因子VIIIa A2亚基残基558-565代表因子IXa相互作用位点。
DOI：
--
发表时间：
1994
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Fay,PJ;Beattie,T;Huggins,CF;Regan,LM
通讯作者：
Regan,LM
人因子 VIII 中亚基间荧光能量转移。
DOI：
--
发表时间：
1989
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Fay,PJ;Smudzin,TM
通讯作者：
Smudzin,TM