Crystal structure of TRAIL-DR5 complex identifies a critical role of the unique frame insertion in conferring recognition specificity

TRAIL is a cytokine that induces apoptosis in a wide variety of tumor cells but rarely in normal cells. It contains an extraordinarily elongated loop because of an unique insertion of 12-16 amino acids compared with the other members of tumor necrosis factor family. Biological implication of the fra me insertion has not been clarified. We have determined the crystal structu re of TRAIL in a complex with the extracellular domain of death receptor DR 5 at 2.2 Angstrom resolution. The structure reveals extensive contacts betw een the elongated loop and DR5 in an interaction mode that would not be all owed without the frame insertion. These interactions are missing in the str uctures of the complex determined by others recently. This observation, alo ng with structure-inspired deletion analysis, identifies the critical role of the frame insertion as a molecular strategy conferring specificity upon the recognition of cognate receptors. The structure also suggests that a bu ilt-in flexibility of the tumor necrosis factor receptor family members is likely to play a general and important role in the binding and recognition of tumor necrosis factor family members.