LIGAND-RECEPTOR INTERACTIONS IN THE TGF-BETA SUPERFAMILY

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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.