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: 10551878
• 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/10551878
• 关键词: Activins; Apolipoproteins; Binding; Biogenesis; Biological Process; Cellular Assay; Collection; Complex; Coupled; Disparate; 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; antagonist; 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：转化生长因子-超家族，包括BMP和激活素，代表了一个不同的集合 对众多生物过程有深刻控制的信号配体。通常，配体是 螺旋桨形状的二硫键二聚体。它们通过与两个类型的I形成三元络合物来发出信号 和两个II型受体，激活下游信号事件。这个集会是由一个数字进行调解的 细胞外蛋白质调节剂直接与配体结合，影响其与细胞的相互作用 感受器。结合X射线结晶学和结合分析以及体外细胞分析， 本实验室的目标是确定配体-受体相互作用的分子机制。 来区分信号。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-受体的相互作用来中和配体。同样，我们的目标是理解 某些配体的N末端前结构域如何使生长因子潜伏并专注于破译 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，并在某些情况下具有生物学意义，甚至比同源二聚体形式更相关。因此， 实验室正在研究配体杂二聚体的结构、功能和合成。在一个完全不同的项目中，我们 正在对载脂蛋白的结构和功能进行表征-目的是了解它们是如何转变的 在脂蛋白颗粒的生物发生中，从无脂状态到脂结合状态。