FIGURE 2.

Scheme of oligomerization of TNFSF₃–TNFRSF₃ complexes. The cell membrane TNFSF (mem TNFSF, often associated as trimer) binds to TNFRSF via the interactions between the TNF homology domain (THD) and cysteine rich domain (CRD), resulting in the formation of TNFSF₃-TNFRSF₃ complex. However, the minimum TNFSF-TNFRSF complex is insufficient to trigger signaling of some TNFRSF members including CD40, CD137, OX40, and GITR. Secondary interaction of the initial trimeric complex leads to oligomerization of the ligand-receptor complexes. The clustering of multiple TNFRSFs is necessary to activate receptor intracellular signaling pathways.