Structural basis for signal initiation by TNF and TNFR

Abstract

Tumor necrosis factor (TNF; tumor necrosis factor ligand superfamily member 2) induces a variety of intracellular signaling pathways including NF-κB activation through the binding to its two receptors, the TNF receptor superfamily member 1A (TNFR1; CD120A) and TNF receptor superfamily member 1B (TNFR2; CD120B). TNF has a crucial role in host defense against infectious diseases and carcinogenesis, but elevated concentrations of TNF cause various autoimmune diseases such as rheumatoid arthritis, Crohn's disease, and ulcerative colitis. For clinical therapy trials, receptor-selective drugs are preferred because the blocking of both TNFRs can cause serious side effects. Crystal structure of the TNF and TNFR2 complex (TNF-TNFR2) was determined at 3.0 Å resolution. Although TNF trimer binds to three TNFR2 molecules similar to the known structure of the lymphotoxin-α (LT-α)-TNFR1 complex, structural comparison between TNFR2 and TNFR1 clearly showed several differences on the ligand-binding interfaces of the two receptors that may be useful information for the design of receptor-selective drugs. Furthermore, it was observed that the TNF-TNFR2 complexes form aggregates on the cell surface, suggesting two-dimensional network models for the signal initiation through TNFR2. Here we describe structural features of the TNF and TNFR superfamilies and the structural basis of the signal initiation triggered by the TNF-TNFR2 complex.