The structure of tumour necrosis factor--implications for biological function.
The three-dimensional structure of TNF has been determined at 0.29 nm using the technique of X-ray crystallography. Published data on site-directed mutagenesis and antibody binding may now be assessed in the light of the structure, thus the links between structure and function for TNF may be addressed. TNF is a compact trimer composed of three identical subunits of 157 amino acids. The main-chain topology for a single subunit is essentially a beta-sandwich structure formed by two anti-parallel beta-pleated sheets. This mainchain fold corresponds to the 'jelly roll' motif observed in viral coat proteins such as VP1, VP2 and VP3 of rhinovirus, or the hemagglutinin molecule of influenza. TNF is the first non-viral protein to contain this motif. The subunits associate tightly about a threefold axis interacting through a simple edge-to-face packing of the beta-sandwich to form the solid, conical shaped trimer. A large number of the residues conserved between the amino acid sequences of TNF and lymphotoxin lie within the beta-sandwich or at the threefold axis of the trimer. This implies the presence of the same beta-sandwich motif in the lymphotoxin monomer and preservation of the edge-to-face mode of trimeric association. The detailed three dimensional structure for TNF explains a wide range of observations, including data on antibody binding and site directed mutagenesis. The currently available evidence points to a region of biological importance situated at the interface between two subunits on the lower half of the trimer.
Jones
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Laboratory of Molecular Biophysics, University of Oxford, UK.
Stuart
D I
DI
Walker
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NP
D000595:Amino Acid Sequence; D001665:Binding Sites; D046911:Macromolecular Substances; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D011487:Protein Conformation; D011956:Receptors, Cell Surface / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha / Q000737:chemistry* / Q000235:genetics / Q000502:physiology; D014961:X-Ray Diffraction
D046911:Macromolecular Substances; D011956:Receptors, Cell Surface; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha