INTERACTIONS OF ACTIVINS AND BMP WITH THEIR RECEPTORS

这项研究的总体目标是了解TGF-β家族配体和细胞表面受体之间分子识别和组装的结构基础。TGF-β配体发挥广泛的生物学功能。参与信号级联的两种类型的受体，每种都具有单个跨膜螺旋和细胞质Ser/Thr激酶结构域，与配体形成大的蛋白质复合物以启动信号传导过程。我们的具体目标是对配体与第一受体的胞外结构域的结合以及其随后与其他受体的复合物如何将信息转导到信号传导途径的下游组分有一个结构上的理解。骨形态发生 BMP是TGF-β配体超家族的一个亚家族。我们将围绕Activin/BMP信号系统来解决这些问题。此外，我们将研究Activin/BMP与其拮抗剂Noggin的相互作用。我们将研究其受体配体结合域的结构。在这项研究中，我们的主要重点是两个方面：1）解码这些配体中特定和常见的基本结构决定因素，2）了解复合物形成后诱导的配体构象变化与生物信号输出。基于不同配体/受体复合物的化学计量比和结合亲和力，我们将建立该过程的热力学和动力学速率。此外，我们将确定与Noggin复合的BMP变体的结构。我相信这些研究的结果将为理解分子识别和受体组装的结构基础提供坚实的基础，从而有助于设计有效的治疗手段， 可用于调节各种神经系统疾病。

The overall objective of the proposed study is to understand the structural basis for molecular recognition and assembly between TGF-beta family ligands and cell surface receptors. The TGF-beta ligands exert a wide range of biological functions. Two types of receptors involved in the signaling cascade, each with a single transmembrane helix and a cytoplasmic Ser/Thr kinase domain, form a large protein complex with the ligand to initiate the signaling process. Our specific goal is to have a structural understanding on how the binding of ligands to the extracellular domain of the first receptor, and its subsequent complex with the other receptor transduces the message to the downstream components of the signaling pathway. Bone morphogenetic proteins (BMP) is a subfamily of TGF-beta ligand superfamily. We will focus on Activin/BMP signaling system to address these questions. In addition, we will study the Activin/BMP interaction with its antagonist Noggin. We will study structures of ligand-binding domain of inhibin receptor. In this study, our primary focus is two-fold: 1) to decode fundamental structural determinants specific and common among those ligands, and 2) to understand conformational changes in the ligand induced upon complex formation with respect to the biological signaling outputs. Based on stoichiometric ratios and binding affinity of different ligand/receptor complexes, we will establish the thermodynamic and kinetic rates of the processes. Additionally, we will determine structures of BMP variants in complex with Noggin. I believe results from these studies will provide a firm basis to understand structural basis for molecular recognition and receptor assembly, from which we can facilitate the design of effective therapeutic means to be used in modulating various hormone-related and neurological diseases.