Structural insight into the signaling and regulation of GDF8 and GDF11

项目摘要：转化生长因子-β家族由33个单独的配体组成，在整个人类中起着重要的作用 生物学。由于它们的生物学重要性，存在多种形式的调控来控制配体信号，其中许多 它们是配体的子集所特有的。本项目将重点关注两个密切相关的信号和调控 相关的转化生长因子-β配体--生长和分化因子8和11。在功能上，GDF8是一个强大的 肌肉质量的负调节因子。因此，人们一直在寻找GDF8的抑制剂来治疗诱导 肌肉肥大，以治疗肌肉萎缩的病理。另一方面，GDF11，其份额为90% 与GDF8相同，在红细胞分化中具有作用，其抑制已被证明能促进红细胞 细胞生产。GDF8和GDF11都通过相似的受体传递信号，并由以下几种受体共同控制 潜伏期和细胞外拮抗剂。然而，我们关于这些机制的信息有限， 调节GDF8和GDF11的分子细节，部分原因是缺乏描述GDF8和GDF11的结构信息 这些互动。总体目标和长期目标是了解 调节GDF8和GDF11信号。我们将采取结构-功能的方法，耦合结构研究(X- 射线结晶学和核磁共振)，结合分析和体外细胞分析。观测时间将延长 在体内，在小鼠模型中使用重组GDF8/11复合体。我们将追求三个具体目标： 将涉及(1)解析GDF8和GDF11与其同源受体的分子细节，(2)表征 GDF8和GDF11的潜伏期及其从潜伏期如何被激活和(3)确定 胞外拮抗剂GAP的结构机制及拮抗作用的确定 GDF8和GDF11。总的来说，这些目标将提供对监管机制的更深层次的理解 GDF8和GDF11信号，最终可用于促进或增强当前的治疗努力 调节配体信号。

Project Summary: The TGF-β family consists of 33 individual ligands with fundamental roles throughout human biology. Due to their biological importance, multiple forms of regulation exist to control ligand signaling, many of which are specific for a subset of ligands. This project will focus on the signaling and regulation of two closely related TGF-β ligands - Growth and Differentiation Factor 8 (GDF8) and GDF11. Functionally, GDF8 is a strong negative regulator of muscle mass. As such, inhibitors to GDF8 have been pursued to therapeutically induce muscle hypertrophy in order to treat muscle-wasting pathologies. On the other hand, GDF11, which shares 90% identity to GDF8, has a role in erythrocyte differentiation where its inhibition has been shown to boost red blood cell production. Both GDF8 and GDF11 signal through similar receptors and are controlled by a combination of latency and extracellular antagonists. However, we have limited information regarding the mechanisms and molecular details that regulate GDF8 and GDF11, in part due to a lack of the structural information describing these interactions. The overall goal and long-term objective is to understand the molecular mechanisms that regulate GDF8 and GDF11 signaling. We will take a structure-function approach, coupling structural studies (X- ray crystallography and NMR) with binding analysis and in vitro cell-based assays. Observations will be extended to in vivo, in mouse models using recombinant GDF8/11 complexes. We will pursue three specific aims which will involve (1) resolving the molecular details of GDF8 and GDF11 with its cognate receptors, (2) characterizing the latent state of GDF8 and GDF11 and deciphering how they are activated from latency and (3) determining the structural mechanism of the extracellular antagonist GASP and determining how antagonism is specific for GDF8 and GDF11. Collectively, these aims will provide a deeper understanding of the mechanism that regulate GDF8 and GDF11 signaling, which can ultimately be used to facilitate or augment current therapeutic efforts to modulate ligand signaling.