STRUCTURAL STUDIES OF TNFL-TNFR COMPLEXES INCLUDING BLYS-BR3

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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. BlyS and April are members of the tumor necrosis factor (TNF) superfamily. They both bind to the receptors TACI and BCMA while only BlyS binds to the receptor BR3. BR3 and BCMA are very divergent members of the TNF receptor (TNFR) superfamily and are the smallest known TNFRs with only 4 and 6 cysteines each, respectively. Overexpression of BLyS has been implicated in the overproduction of peripheral B-cells and in the development of systemic lupus erythematosus-like symptoms in animal models. These symptoms can be alleviated with treatment by fusion proteins composed of an Fc domain fused to the extracellular domain (ECD) of TACI or BR3. April also is involved in cellular proliferation and is overexpressed by some tumor types. Determining the high-resolution structure of the BLyS-BR3 complex will give us insights into the specificity of BR3 for BLyS over April, will allow determination of the core structural components of TNF-TNFR superfamily signaling, and will assist in development agents to regulate BLyS signaling which may have therapeutic potential to control lupus and other auto-immune disorders.