Structural/functional characterization of TGFβ superfamily signaling and regulation

项目概述：TGF-β超家族，包括BMP和激活素，代表了多样化的集合 信号配体对许多生物过程具有深远的控制作用。通常，配体是 具有螺旋桨状形状的二硫键键二聚物。它们通过与两个I型分子形成三元复合物来发出信号 和两个II型受体，其激活下游信号事件。这个集合是由一个数字 直接与配体结合以影响它们与细胞内蛋白质的相互作用的细胞外蛋白质调节剂。 受体。使用X射线晶体学和结合分析结合体外细胞测定的组合， 我们实验室的目标是确定配体-受体相互作用的分子机制， 区分信令。此外，我们的实验室正在表征细胞外 拮抗剂，其通过阻断配体-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-末端前结构域如何使生长因子潜伏， 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，并且在某些情况下具有生物学相关性，甚至比同二聚体形式更重要。因此 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转变 在脂蛋白颗粒的生物发生中从脂质游离状态到脂质结合状态。

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.