Solution of the Structure of the TNF-TNFR2 Complex

Structural differences in the binding of tumor necrosis factor to its two receptors may aid in the development of receptor-specific therapeutics. Structural Differences The proinflammatory cytokine tumor necrosis factor (TNF) functions in the immune response; however, TNF also plays a pathophysiological role in diseases such as rheumatoid arthritis and Crohn’s disease. The effects of TNF are mediated by TNF receptor 1 (TNFR1) and TNFR2; whereas TNFR1 is ubiquitously expressed, TNFR2 is mostly restricted to cells of the immune system. Currently available therapies that block TNF include monoclonal antibodies against TNF and a soluble form of TNFR2; however, these therapies can result in serious side effects, some of which may be due to their nonselective effects. Here, Mukai et al. solved the structure of TNF in complex with TNFR2 and found differences between the ligand-binding interface of TNFR2 and that of TNFR1, whose structure is known. The authors also observed the formation of TNF-TNFR2 aggregates on the surface of transfected cells, which may be required for signal initiation. Solution of the TNFR2 structure may aid in the development of receptor-specific therapies. Tumor necrosis factor (TNF) is an inflammatory cytokine that has important roles in various immune responses, which are mediated through its two receptors, TNF receptor 1 (TNFR1) and TNFR2. Antibody-based therapy against TNF is used clinically to treat several chronic autoimmune diseases; however, such treatment sometimes results in serious side effects, which are thought to be caused by the blocking of signals from both TNFRs. Therefore, knowledge of the structural basis for the recognition of TNF by each receptor would be invaluable in designing TNFR-selective drugs. Here, we solved the 3.0 angstrom resolution structure of the TNF-TNFR2 complex, which provided insight into the molecular recognition of TNF by TNFR2. Comparison to the known TNFR1 structure highlighted several differences between the ligand-binding interfaces of the two receptors. Additionally, we also demonstrated that TNF-TNFR2 formed aggregates on the surface of cells, which may be required for signal initiation. These results may contribute to the design of therapeutics for autoimmune diseases.

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