INTERACTIONS OF ACTIVINS AND BMP WITH THEIR RECEPTORS

激活素和 BMP 与其受体的相互作用

• 批准号: 6849106
• 负责人: SENYON CHOE
• 金额: $ 18.01万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-12-01 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6849106
• 关键词: SDS polyacrylamide gel electrophoresis; X ray crystallography; activins; binding sites; biological signal transduction; bone morphogenetic proteins; cell surface receptors; inhibin; ligands; nuclear magnetic resonance spectroscopy; polymerase chain reaction; protein protein interaction; protein structure function; surface plasmon resonance; transforming growth factors

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.

本研究的总体目标是了解tgf - β家族配体与细胞表面受体之间分子识别和组装的结构基础。tgf - β配体具有广泛的生物学功能。参与信号级联的两种类型的受体，每一种都具有单个跨膜螺旋和细胞质Ser/Thr激酶结构域，与配体形成一个大的蛋白质复合物来启动信号传导过程。我们的具体目标是对配体与第一受体的细胞外结构域的结合及其随后与其他受体的复合物如何将信息转导到信号通路的下游组分有一个结构上的理解。骨形成