INTERACTIONS OF ACTIVINS AND BMP WITH THEIR RECEPTORS

这项拟议研究的总体目标是了解转化生长因子-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。转化生长因子-β配体具有广泛的生物学功能。参与信号级联的两种受体，每种都有一个跨膜螺旋和一个细胞质的丝氨酸/苏氨酸激酶域，与配体形成一个大的蛋白质复合体，启动信号传递过程。我们的具体目标是对配体与第一个受体的胞外区域以及随后与另一个受体的复合体如何将信息传递到信号通路的下游组件有一个结构性的了解。骨形态发生学 骨形态发生蛋白(BMP)是转化生长因子β配体超家族的一个亚家族。我们将重点研究Activin/BMP信号系统来解决这些问题。此外，我们还将研究激活素/骨形态发生蛋白与其拮抗剂Noggin的相互作用。我们将研究抑制素受体的配体结合域的结构。在这项研究中，我们的主要关注点有两个：1)破译这些配体中特有的和共同的基本结构决定因素；2)了解络合物形成时配体相对于生物信号输出的构象变化。基于不同配体/受体络合物的化学计量比和结合亲和力，我们将建立过程的热力学和动力学速率。此外，我们还将确定与Noggin形成的复合体中BMP变体的结构。我相信这些研究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。 用于调节各种与激素有关的疾病和神经系统疾病。

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.