STRUCTURAL SUDIES ON FIBRINGEN AND FIBRIN

两个压倒一切的问题使纤维蛋白原-纤维蛋白领域的所有工作者团结起来： 纤维蛋白（原）单位是如何包装在纤维蛋白聚合物中的， 把它们结合在一起的力量 我们正采取双管齐下的办法， 这些问题，一个是基于蛋白质的进化相互依赖性， 结构和功能，另一种基于合成肽， 系统中最保守的特征。 同时抱定 自然对脊椎动物血液凝固的方式和时间感兴趣 将军是发明的。 我们的建议是基于这样一个概念，即只有我们 了解一个系统的历史，我们才能智能地操纵它。 具体目标包括进一步表征纤维蛋白原， 七鳃鳗，现存最原始的脊椎动物， 已知有凝血酶-纤维蛋白原分子的生物。 我们计划 为了完成β和α链克隆的cDNA序列， 并继续研究肽结合和纤维蛋白聚合。 从这些研究中获得的知识将应用于两个不同的领域， 领域 首先，哺乳动物和七鳃鳗纤维蛋白原的特征 共同点必须是至关重要的功能，因为他们已经证明， 保存了超过4亿年 我们计划合成世界上 纤维蛋白原分子的严格保守部分，以确定 用于聚合和其他相互作用的特定位点。 二、特点 七鳃鳗和哺乳动物常见的纤维蛋白原也是最有可能 存在于更原始的生物中，其中纤维蛋白原尚未被发现。 found. 我们打算使用这些特征的遗传等价物（即， 合适的限制性片段和合成寡核苷酸）进行筛选 从原脊索动物和那些无脊椎动物制备的基因组文库 被认为与脊椎动物系关系最密切。 的焦点 搜索将针对可能已经 从不同的来源组装在港口的建设 纤维蛋白原分子 这项研究还包括寻找 其他血浆蛋白质的前因基因通常被认为是排他性的 脊椎动物，包括白蛋白，转铁蛋白，血浆铜蓝蛋白和 α 2-巨球蛋白

Two overriding questions unify all workers in the fibrinogen-fibrin field: how are the fibrin(ogen) units packed in the fibrin polymer, and what are the forces that hold them together? We are taking a twofold approach to these problems, one based on the evolutionary interdependence of protein structure and function, the other based on synthetic peptides patterned on the most conserved features of the system. At the same time we are naturally interested in how and when vertebrate blood coagulation in general was invented. Our proposal is based on the notion that only if we understand the history of a system can we intelligently manipulate it. Specific goals include further characterization of fibrinogen from the lamprey, the most primitive vertebrate extant and the most primitive creature known to have a thrombin-clottable fibrinogen molecule. We plan to complete the cDNA sequences of clones for the beta and alpha chains, as well as continue studies on peptide binding and fibrin polymerization. Knowledge gained from these studies will be applied in the two different realms. First, those features that mammalian and lamprey fibrinogens have in common must be vital to function, as evidenced by their having been conserved for over 400 million years. We plan to synthesize the most rigorously conserved parts of the fibrinogen molecule in order to identify specific sites for polymerization and other interactions. Second, features common to lamprey and mammalian fibrinogens are also those most likely to exist in even more primitive creatures, among whom fibrinogen has yet to be found. We intend to use the genetic equivalents of those features (i.e., appropriate restriction fragments and synthetic oligonucleotides) to screen genomic libraries prepared from protochordates and those invertebrates thought to be most closely related to the vertebrate line. The focus of the search will be on exon or domainal equivalents that may have been assembled from diverse sources in the construction of the portotype fibrinogen molecule. The study also encompasses a search for the antecedent genes of other plasma proteins usually thought to be exclusive to vertebrates, including albumin, transferrin, ceruloplasmin and alpha-2-macroglobulin.