TERTIARY STRUCTURES OF ACTIVIN AND ACTIVIN RECEPTORS

拟议研究的长期目标是了解信号是如何 通过活细胞的细胞膜传递。神经肽类/蛋白质类 与它们的受体结合发挥不同的生物学功能， 为研究信号转导机制提供了一个良好的系统。 受体通常是跨膜蛋白，具有单个 跨膜螺旋一个共同的主题开始出现在那些 参与信号转导的受体。很明显 配体与其受体的细胞外结构域的结合是配体与其受体的细胞外结构域的结合。 信号的第一步。然而，结构上的理解， 然后将结合传递到信号传导的下游组分 路径是非常必要的。一种观点认为配体结合 与受体的结合诱导应答的寡聚化（同源或异源）， 受体。这一概念构成了信令的基础 生长因子以及生长因子样细胞因子的机制， 肿瘤坏死因子。它通常被称为“受体聚集”， 已经提出用于许多已知的细胞因子受体。晶体结构 人生长因子/受体复合物与肿瘤坏死 因子/受体复合物支持“受体聚集”的想法。 MHCII的晶体结构也表明， 肽/MHC II复合物诱导受体二聚化。在我们提出的 研究中，我们计划集中在激活素和激活素/受体复合物。激活素 以独特的方式与两种受体相互作用。不像大多数 已知是酪氨酸磷酸化的跨膜受体，这组 是丝氨酸/苏氨酸激酶活性。此外，只有类型 已知II型受体与激活素结合，尽管I型受体与激活素的结合不稳定。 受体与II型受体与配体的复合物， 必需的.这两种类型的受体在其各自的细胞内都具有丝氨酸激酶活性。 胞质结构域，并且两者的活性都是信号传导所需的。 激活素的重组形式和激活素的配体结合结构域 受体现在可以大量获得。化学和生物物理 激活素及其受体的特性可能提供线索， 更好地理解互动的本质。晶体结构 激活素及其与受体的复合物将通过X射线研究 晶体学方法激活素的三维结构， 激活素与其受体的复合物将提供良好的模型， 以原子分辨率定义绑定接口。构象 II型受体响应激活素结合的变化可能触发 信号通路的进一步级联，提供了一个重要线索， 理解信号机制的结构基础， 膜的定义神经肽结合特异性的原子模型 如激活素和促性腺激素释放激素也会促进 设计有效和持久的拟肽药物， 可用于调节各种与乳腺癌相关的疾病。

The long-term goal of the proposed study is to understand how signal is transduced across the membrane of a living cell. Neuropeptides/proteins bind to their receptors to exert different biological functions, providing a good system to study the mechanism of signal transduction. The receptors are often transmembrane proteins with a single transmembrane helix. A common theme begins to emerge among those receptors involved in signal transduction. It is apparent that the binding of a ligand to the extracellular domain of its receptor(s) is the first step of signaling. However, structural understanding of how this binding is then transduced to the downstream components of signaling pathway is much needed. One school of thought is that the ligand binding to a receptor induces an oligomerization (homo- or hetero-) of responsive receptors. This notion forms the underlying basis for the signaling mechanism of growth factor as well as growth factor-like cytokines such as tumor necrosis factor. It is commonly called "receptor clustering" and has been proposed for many known cytokine receptors. Crystal structures of human growth factor/receptor complex and tumor necrosis factor/receptor complex support the idea of "receptor clustering". Crystal structure of MHC II also suggests a possibility that the peptide/MHC II complex induces dimerization of receptors. In our proposed study, we plan to focus on activin and activin/receptor complex. Activin interacts with two types of receptors in a unique manner. Unlike most transmembrane receptors known to be tyrosine phosphorylating, this group of receptors is serine/threonine kinase active. In addition, only type II receptor is known to bind to activin although the binding of type I receptor with the complex of type II receptor with the ligand is required. Both types of receptors have serine kinase activity in their cytoplasmic domains, and the activity of both are required for signaling. Recombinant forms of activin and the ligand-binding domain of activin receptors are now available in quantity. Chemical and biophysical characterization of activin and its receptor may provide a clue to a better understanding of the nature of interaction. Crystal structures of activin and its complex with the receptor will be studied by X-ray crystallographic methods. The three-dimensional structures of activin and the complex of activin with its receptor would provide a good model, defining he binding interface at atomic resolution. Conformational changes of type II receptor responding to activin binding may trigger the further cascade of signaling pathway, providing an important clue is understanding the structural basis of signaling mechanism across the membrane. Atomic models defining the binding specificity of neuropeptides such as activin and gonadotropin-releasing hormone would also facilitate the design of effective and long-lasting peptidomimetic drugs that would be useful in modulating various hormone-related diseases.