Structural/functional characterization of TGFβ superfamily signaling and regulation

TGFβ 超家族信号传导和调节的结构/功能表征

• 批准号: 10094061
• 负责人: THOMAS B THOMPSON
• 金额: $ 56.18万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10094061
• 关键词: Activins; Apolipoproteins; Binding; Biogenesis; Biological; Biological Process; Cellular Assay; Collection; Complex; Coupled; Event; Extracellular Protein; Growth Factor; Human Biology; In Vitro; Laboratories; Ligands; Lipid Binding; Lipids; Lipoproteins; Mediating; Molecular; N-terminal; Public Health; Regulation; Research; Role; Shapes; Signal Transduction; Signaling Molecule; Structure; Therapeutic Intervention; Transforming Growth Factor beta; X-Ray Crystallography; dimer; disulfide bond; extracellular; human disease; insight; particle; protein phosphatase inhibitor-2; receptor

Project Summary: The TGF- superfamily, which includes BMPs and activins, represents a diverse collection of signaling ligands that have profound control over numerous biological processes. Typically, ligands are disulfide-bonded dimers with a propeller-like shape. They signal by forming a ternary complex with two type I and two type II receptor, which activates downstream signaling events. This assembly is mediated by a number of extracellular protein modulators which directly bind to the ligands to impact their interaction with the cellular receptors. Using a combination of X-ray crystallography and binding analysis coupled with in vitro cellular assays, the objective of our laboratory is to define the molecular mechanisms of ligand-receptor interactions incorporated to differentiate signaling. Furthermore, our laboratory is characterizing the interactions of extracellular antagonists, which neutralize ligands by blocking ligand-receptors interactions. Similarly, we aim to understand how the N-terminal prodomain of certain ligands renders the growth factor latent and are focused on deciphering the molecular mechanisms of activation. In addition, recent research has shown that heterodimeric ligands can form and are biologically relevant in certain cases, even more so than the homodimeric versions. Thus, the laboratory is investigating the structure, function and synthesis of ligand heterodimers. In a disparate project, we are characterizing the structure and function of apolipoproteins – with the intent to understand how they transition from a lipid free state to a lipid bound state in the biogenesis of lipoprotein particles.

项目摘要：包括BMP和激活蛋白在内的TGF-超家族代表多样化的收藏 对众多生物过程有深远控制的信号配体。通常，配体是 二硫键二聚体具有螺旋桨状形状。它们是通过形成两种I的三元复合物来发出信号的 和两个II型接收器，该接收器激活下游信号事件。该组件由一个数字介导 细胞外蛋白调节剂的直接结合，以影响其与细胞的相互作用 受体。使用X射线晶体学和结合分析的结合，结合体外细胞测定法 我们实验室的目的是定义配体相互作用的分子机制 区分信号。此外，我们的实验室正在表征细胞外的相互作用 拮抗剂，通过阻断配体 - 受体相互作用来中和配体。同样，我们的目标是了解 某些配体的N末端prodomain如何使生长因子潜在并专注于破译 激活的分子机制。此外，最近的研究表明，异二聚体配体可以 形式并且在某些情况下与生物学相关，甚至比同二聚体版本更重要。那， 实验室正在研究配体异二聚体的结构，功能和合成。在一个不同的项目中，我们 正在表征载脂蛋白的结构和功能 - 目的是了解它们如何过渡 从脂蛋白颗粒的生物发生中，从无脂质状态到脂质结合状态。