LIGAND-RECEPTOR INTERACTIONS IN THE TGF-BETA SUPERFAMILY

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 我们正在研究异四聚体信号复合体的合作组装的结构基础，该复合体调节细胞内稳态，并与多种病理生理有关，如器官纤维化和癌症。本课题组已经确定了二聚体信号配体和一对受体胞外结构域的二元复合体的结构，但第二对受体协同募集到这个复合体中的结构基础到目前为止还不清楚。从我们初步的低分辨率模型中，我们已经确定了三元复合体中几个新的、意想不到的相互作用，并通过对不同受体的功能分析证实了这些作用。组装的信号复合体的结构将为合理设计抗纤维化和抗癌治疗药物提供基础，并引起广大细胞信号界的极大兴趣。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We are studying the structural basis for the cooperative assembly of a heterotetrameric signaling complex that regulates cellular homeostasis and has been implicated in multiple pathophysiologies such as organ fibrosis and cancers. The structure of the binary complex of the dimeric signal ligand and one pair of receptor extracellular domains has been determined by our group, but the structural basis for the cooperative recruitment of the second pair of receptors into this complex has remained unknown up until now. We have identified several novel, unanticipated interactions within the ternary complex from our preliminary low resolution model and confirmed these by functional analyses of variant receptors. The structure of the assembled signaling complex will provide the basis for rational design of anti-fibrotic and anti- cancer therapeutics and be of tremendous interest to the cell signaling community at large.