PROTEIN MOLECULAR BIOLOGY OF TISSUE FACTOR

组织因子（TF）是主要的和关键的分子， 启动凝血丝氨酸蛋白酶级联。 表示为 细胞表面跨膜受体，它启动组装的 二进制复杂TF VIIa和指导的有效组装的三元 产生活性丝氨酸蛋白酶Xa和IXa的复合物。 我们将 通过模型详细阐述TF功能的结构基础- 指导性定点诱变结合三个 三维结构数据来阐明蛋白质分子生物学 TF和该受体功能的基础。 这些目标将 （i）定义关键残基并表征功能性 替换以发展结构到功能的解释 识别和高亲和力结合VII的分子基础， （ii）研究底物X和IX的结构基础 协调和特异性蛋白水解激活;（iii）探索 TF在VII激活中的结构作用;（iv）探索 细胞和磷脂膜上的弹性和间距， 调节TF调节的起始复合物的效率;（v） 探索TF二聚化在调节 起始复合体 这些信息将是必要的解释 来自晶体学和高分辨率NMR的三维数据。 此外，还讨论了TF的基本性质和 子结构的函数类将提供详细的分析， 细胞因子/造血细胞因子家族模型的结构生物学 生长因子受体。

Tissue factor (TF) is the primary and pivotal molecule responsible for initiation of the coagulation serine protease cascades. Expressed as a cell surface transmembrane receptor it initiates the assembly of the binary complex TF VIIa and guides the efficient assembly of the ternary complex that produces the active serine proteases Xa and IXa. We will address in detail the structural basis for TF function through model- guided site-directed mutagenesis coupled with integration with three dimensional structural data to elucidate the protein molecular biology of TF and the basis for the function of this receptor. The goals will be to: (i) define the critical residues and characterize functional replacements to develop structure to function interpretations of the molecular basis for the recognition and high affinity binding of VII and VIIa; (ii) investigate the structural basis of substrate X and IX coordination and specific proteolytic activation; (iii) explore the structural role of TF in the activation of VII; (iv) explore the role of flexibility and spacing above the cell and phospholipid membrane in regulation of the efficiency of the TF regulated initiation complex; (v) explore the role of TF dimerization in regulation of the efficiency of the initiation complex. This information will be necessary to interpret the three dimensional data from crystallography and high resolution NMR. In addition, the fundamental properties of TF and the assignment of classes of function to substructure will provide a detailed analysis of the structural biology of a model of the family of Cytokine/Hematopoietic Growth Factor Receptors.