title: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces death receptor 5 networks that are highly organized.
abstract: Recent evidence suggests that TNF-related apoptosis-inducing ligand (TRAIL), a death-inducing cytokine with anti-tumor potential, initiates apoptosis by re-organizing TRAIL receptors into large clusters, although the structure of these clusters and the mechanism by which they assemble are unknown. Here, we demonstrate that TRAIL receptor 2 (DR5) forms receptor dimers in a ligand-dependent manner at endogenous receptor levels, and these receptor dimers exist within high molecular weight networks. Using mutational analysis, FRET, fluorescence microscopy, synthetic biochemistry, and molecular modeling, we find that receptor dimerization relies upon covalent and noncovalent interactions between membrane-proximal residues. Additionally, by using FRET, we show that the oligomeric structure of two functional isoforms of DR5 is indistinguishable. The resulting model of DR5 activation should revise the accepted architecture of the functioning units of DR5 and the structurally homologous TNF receptor superfamily members.
authors.affiliation: Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Valley
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Lewis
authors.forename: Deepti J
authors.initials: DJ
authors.lastname: Mudaliar
authors.forename: Jason D
authors.initials: JD
authors.lastname: Perlmutter
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Braun
authors.forename: Christine B
authors.initials: CB
authors.lastname: Karim
authors.forename: David D
authors.initials: DD
authors.lastname: Thomas
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Brody
authors.forename: Jonathan N
authors.initials: JN
authors.lastname: Sachs
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D031541:Fluorescence Resonance Energy Transfer; D057809:HEK293 Cells; D006801:Humans; D019169:Jurkat Cells; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D055503:Protein Multimerization / Q000502:physiology*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*
chemical_list: D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human