Structural principles of tumor necrosis factor superfamily signaling

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...

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Veröffentlicht in:Science signaling Jg. 11; H. 511
Hauptverfasser: Vanamee, Éva S, Faustman, Denise L
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 02.01.2018
Schlagworte:
Animals
Antibodies - chemistry
Antibodies - metabolism
Cell Death
Cell Proliferation
Humans
Ligands
Mice
Protein Binding
Protein Conformation
Receptors, Tumor Necrosis Factor - antagonists & inhibitors
Receptors, Tumor Necrosis Factor - chemistry
Receptors, Tumor Necrosis Factor - metabolism
Signal Transduction
Tumor Necrosis Factor-alpha - antagonists & inhibitors
Tumor Necrosis Factor-alpha - chemistry
Tumor Necrosis Factor-alpha - metabolism
ISSN:1937-9145, 1937-9145
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Zusammenfassung: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.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
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ISSN:1937-9145
1937-9145
DOI:10.1126/scisignal.aao4910