Apoptosis-inducing ligand 2 (Apo2L,TRAIL)/death receptor 5 (DR5) complex
Homo sapiens (human)
The cells of a multicellular organism form a highly organized community. The number of cells in this community is tightly regulated, not only by controlling the rate of cell division, but also by controlling the rate of cell death. As cells are no longer necessary, they commit suicide by activating an intracellular death program. This process is therefore called programmed cell death, generally apoptosis. Apoptosis is important for proper development and homeostasis. Apoptosis-inducing ligand 2 (Apo2L, also called TRAIL), a member of the tumor necrosis factor (TNF) family, triggers apoptosis in a variety of human tumor cell lines but not in normal cells. Apo2L/TRAIL binds to related, cysteine-rich receptors that contain cytoplasmic death domains. Oligomerization of these death domains, triggered through ligand-induced receptor trimerization, generates homophilic interaction surfaces for death domain-containing adaptor proteins. These adaptor proteins engage in turn initiator caspases, leading to subsequent activation of effector caspases that execute apoptotic death of the cell.
The crystal structure of the complex between Apo2L and the extracellular domain of DR5, a member of the TNF receptor (TNFR) superfamily, is reported here. The structure shows three extended DR5 molecules nestled into long crevices between pairs of monomers of homotrimeric Apo2L molecules. The interface is divided into two distinct patches, one near the bottom of the complex close to receptor cell surface and one near the top. Both patches contain residues that are essential for high-affinity binding. A comparison to the structure of the complex between Apo2L and another receptor suggests that the patch near the top is generally important for binding in the TNFR superfamily and the patch near the bottom control the specificity and cross-reactivity among the superfamily members.
Protein Data Bank (PDB)
Hymowitz, S.G. Christinger, H.W. Fuh, G. Ultsch, M. O'Connell, M. Kelley, R.F. Ashkenazi, A. de Vos, A.M.; "Triggering cell death: the crystal structure of Apo2L/TRAIL in a complex with death receptor 5."; Mol.Cell; (1999) 4:563-571 PubMed:10549288.
author: Aki Nagata