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

基本信息

批准号：
10335177
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
项目类别：
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

项目摘要

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：TGF-β 超家族包括 BMP 和激活素，代表了一个多样化的集合信号配体对许多生物过程具有深刻的控制作用。具有螺旋桨形状的二硫键二聚体通过与两个 I 型形成三元复合物来发出信号。和两种 II 型受体，激活下游信号传导事件。该组装由许多介导。细胞外蛋白调节剂直接与配体结合以影响其与细胞的相互作用结合使用 X 射线晶体学和结合分析以及体外细胞测定，我们实验室的目标是定义配体-受体相互作用的分子机制此外，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。某些配体的 N 端前结构域如何使生长因子处于潜伏状态并重点破译此外，最近的研究表明异二聚配体可以。在某些情况下形成并具有生物学相关性，甚至比同源二聚体版本更相关。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 - 旨在了解它们如何转变在脂蛋白颗粒的生物发生过程中从脂质游离状态到脂质结合状态。