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.

项目总结：TGF-超家族包括bmp和激活素，是一个多样化的集合