Cloning of cDNA and genomic DNA for human von Willebrand factor.
Cloning of cDNA and genomic DNA for human von Willebrand factor.
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克隆人血管性血友病因子的 cDNA 和基因组 DNA。
DOI：
10.1101/sqb.1986.051.01.063
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发表时间：
1986
期刊：
影响因子：
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通讯作者：
Titani,K
中科院分区：
文献类型：
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作者：
Sadler,JE;Shelton-Inloes,BB;Sorace,JM;Titani,K
人血管性血友病因子（vWF）是一种重要的止血糖蛋白，存在于血小板颗粒、内皮下结缔组织和血浆中，浓度为10 μ g/ml。它由内皮细胞（Jaffe et al. 1973，1974）和巨核细胞（Nachman et al. 1977; Sporn et al. 1985）合成。vWF的生物合成相当复杂。主要的翻译产物似乎是一种超过300，000道尔顿的多肽，其通过二硫键形成在内质网中迅速二聚化。二聚体进一步聚合成一系列同源多聚体，范围从二聚体到超过10，000，000道尔顿的物质。多聚体的形成与氨基末端75-100-kD肽的去除有关（Lynch et al. 1983;瓦格纳和Marder 1983; Fay et al. 1986）、无机硫酸盐的掺入（布朗宁et al. 1983）、糖基化（瓦格纳和Marder 1983，1984）和额外的二硫键形成（瓦格纳et al. 1985，1986）。在内皮细胞中，成熟vWF储存在称为韦伯-帕拉德小体的独特细胞器中（韦伯和帕拉德，1964;瓦格纳等人，1982）。其在血液中的浓度随着对各种刺激的反应而增加，包括雌激素、肾上腺素能药物和加压素类似物（Bloom 1979）。vWF不是一种酶，但通过几种结合相互作用参与止血。它是正常血小板粘附到血管内皮损伤区域所必需的，在血小板受体和内皮下结缔组织成分之间形成桥梁。在存在利托那肽（一种抗生素）的情况下，vWF与血小板质膜上的糖蛋白Ib结合（Jenkins et al. 1976）。遗传性糖蛋白Ib缺乏症，称为伯纳德-苏利尔综合征，会导致严重出血，这可能是由于血小板粘附性差造成的。已被凝血酶或其他血小板激动剂激活的血小板可通过第二受体（糖蛋白IIb/IIIa复合物）与vWF结合。纤维蛋白原和纤连蛋白与vWF竞争后者的这些位点，vWF-糖蛋白IIb/IIIa相互作用的生理学意义尚未完全了解（Pietu et al. 1984; Havertick et al. 1985; Plow et al. 1985）。vWF结合的内皮下成分可能是胶原蛋白（Santoro 1981），尽管也有报道与无胶原蛋白的细胞外基质结合（瓦格纳et al. 1984）。最后，vWF与因子VIII结合，因子VIII约占循环vWF质量的1-2070。这种相互作用对于正常的因子VIII存活是必需的（图德纳姆等，1982）。患有严重的von WiUebrand病的个体遭受皮肤粘膜和胃肠道出血，其类似于血小板功能障碍。然而，如果vWF水平足够低，则可能存在因子VIII的继发性缺乏，并且此类患者还可能具有典型血友病A特征性的软组织出血和关节积血。因子VIII和vWF之间的这种关系产生了一种令人困惑的命名法，其中”因子VIII”指的是任一种蛋白质，也有人认为vWF是因子VIII的前体（综述见Sadler和Davie 1986）。yon Willebrand病是世界范围内最常见的遗传性出血性疾病之一，患病率至少为125/100万。然而，大多数受影响的人症状轻微，严重的疾病仅影响百万分之0.5-3。在大多数情况下，这种疾病表现为常染色体显性遗传，但在一些家庭中，只有纯合子或双杂合子个体有症状。家谱...
Human von Willebrand factor (vWF) is an essential hemostatic glycoprotein that is found in platelet agranules, in subendothelial connective tissue, and in plasma at a concentration of 10 gg/ml. It is synthesized by endothelial cells (Jaffe et al. 1973, 1974) and also by megakaryocytes (Nachman et al. 1977; Sporn et al. 1985). The biosynthesis of vWF is quite complicated. The primary translation product appears to be a polypeptide of over 300,000 daltons that rapidly dimerizes in the endoplasmic reticulum by disulfide bond formation. The dimers undergo further polymerization into a series of homologous multimers ranging from the dimer up to species of over 10,000,000 daltons. Multimer formation is associated with the removal of an amino-terminal 75-100-kD peptide (Lynch et al. 1983; Wagner and Marder 1983; Fay et al. 1986), the incorporation of inorganic sulfate (Browning et al. 1983), glycosylation (Wagner and Marder 1983, 1984), and additional disulfide bond formation (Wagner et al. 1985, 1986). In endothelial cells, mature vWF is stored in unique organelles called Weibel-Palade bodies (Weibel and Palade 1964; Wagner et al. 1982). Its concentration in blood increases in response to a variety of stimuli, including estrogens, adrenergic agents, and vasopressin analogs (Bloom 1979). vWF is not an enzyme, but participates in hemostasis through several binding interactions. It is required for normal platelet adhesion to areas of damage to the vascular endothelium, forming a bridge between platelet receptors and components of the subendothelial connective tissue. In the presence of ristocetin (an antibiotic), vWF binds to glycoprotein Ib on the platelet plasma membrane (Jenkins et al. 1976). Inherited deficiency of glycoprotein Ib, called Bernard-Soulier syndrome, causes severe bleeding that is probably due to poor platelet adhesion. Platelets that have been activated with thrombin or other platelet agonists can bind vWF through a second receptor, the glycoprotein IIb/IIIa complex. Fibrinogen and fibronectin compete with vWF for these latter sites, and the physiological significance of the vWF-glycoprotein IIb/IIIa interaction is not completely understood (Pietu et al. 1984; Haverstick et al. 1985; Plow et al. 1985). The component of the subendothelium to which vWF binds is probably collagen (Santoro 1981), although binding to collagen-free extracellular matrix has also been reported (Wagner et al. 1984). Finally, vWF binds to factor VIII, which constitutes approximately 1-2070 of the mass of circulating vWF. This interaction is necessary for normal factor VIII survival (Tuddenham et al. 1982).These binding properties account for the symptoms of inherited vWF deficiency. Individuals with severe von WiUebrand disease suffer from mucocutaneous and gastrointestinal bleeding that mimics platelet dysfunction. However, if the level of vWF is sufficiently low, there may be a secondary deficiency of factor VIII, and such patients can also have soft tissue bleeding and hemarthroses that are characteristic of classical hemophilia A. This relationship between factor VIII and vWF gave rise to a confusing nomenclature in which" factor VIII" referred to either protein and also to the proposal that vWF was a precursor of factor VIII (for review, see Sadler and Davie 1986). yon Willebrand disease is one of the most common inherited bleeding disorders worldwide, with a prevalence of at least 125 per million. However, most of those affected have mild symptoms, and severe disease affects only 0.5-3 per million. In most cases, the disorder shows autosomal dominant inheritance, but in some families, only homozygous or doubly heterozygous individuals have symptoms. Pedigrees …