The three-dimensional structure of recombinant human lymphotoxin (residues 24-171 of the mature protein) has been determined by x-ray crystallography at 1.9-Å resolution (Rcryst = 0.215 for I > 3σ(I)). Phases were derived by molecular replacement using tumor necrosis factor (TNF-α) as a search model. Like TNF-α, lymphotoxin (LT) folds to form a "jellyroll" β-sheet sandwich. Three-fold related LT subunits form a trimer stabilized primarily by hydrophobic interactions. A cluster of 6 basic residues around the 3-fold axis may account for the acid lability of the trimer. Although the structural cores of TNF-α and LT are similar, insertions and deletions relative to TNF-α occur in loops at the "top" of the LT trimer and significantly alter the local structure and the overall shape of the molecule. The structure of the "base" of the trimer is highly conserved. The sites of two mutations (Asp-50 and Tyr-108) that abolish the cytotoxicity of LT are contained within poorly ordered loops of polypeptide chain that flank the cleft between neighboring subunits at the base of the molecule, suggesting that the receptor recognizes an intersubunit binding site.
|Number of pages
|Journal of Biological Chemistry
|Published - Feb 5 1992