ReviewBiochemistry

Structural principles of tumor necrosis factor superfamily signaling

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Sci. Signal.  02 Jan 2018:
Vol. 11, Issue 511, eaao4910
DOI: 10.1126/scisignal.aao4910

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Gloss

Tumor necrosis factor (TNF) superfamily pathways regulate cell proliferation, cell death, and morphogenesis. TNF superfamily receptors mediate various cancers and immune-mediated diseases. Understanding of the mechanisms of TNF superfamily signaling and the structure and geometry of ligands, receptors, and their interactions is essential to designing effective agonist and antagonist drugs. In this review, consisting of four figures, one table, and 96 references, we discuss our current understanding of TNF ligand-receptor conformations and how this informs signaling and the design of current and prospective therapeutics.

Abstract

The tumor necrosis factor (TNF) ligand and receptor superfamilies play an important role in cell proliferation, survival, and death. Stimulating or inhibiting TNF superfamily signaling pathways is expected to have therapeutic benefit for patients with various diseases, including cancer, autoimmunity, and infectious diseases. We review our current understanding of the structure and geometry of TNF superfamily ligands, receptors, and their interactions. A trimeric ligand and three receptors, each binding at the interface of two ligand monomers, form the basic unit of signaling. Clustering of multiple receptor subunits is necessary for efficient signaling. Current reports suggest that the receptors are prearranged on the cell surface in a “nonsignaling,” resting state in a large hexagonal structure of antiparallel dimers. Receptor activation requires ligand binding, and cross-linking antibodies can stabilize the receptors, thereby maintaining the active, signaling state. On the other hand, an antagonist antibody that locks receptor arrangement in antiparallel dimers effectively blocks signaling. This model may aid the design of more effective TNF signaling–targeted therapies.

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