title: Open and closed conformations of the isolated transmembrane domain of death receptor 5 support a new model of activation.
abstract: It has long been presumed that activation of the apoptosis-initiating Death Receptor 5, as well as other structurally homologous members of the TNF-receptor superfamily, relies on ligand-stabilized trimerization of noninteracting receptor monomers. We and others have proposed an alternate model in which the TNF-receptor dimer-sitting at the vertices of a large supramolecular receptor network of ligand-bound receptor trimers-undergoes a closed-to-open transition, propagated through a scissorslike conformational change in a tightly bundled transmembrane (TM) domain dimer. Here we have combined electron paramagnetic resonance spectroscopy and potential-of-mean force calculations on the isolated TM domain of the long isoform of DR5. The experiments and calculations both independently validate that the opening transition is intrinsic to the physical character of the TM domain dimer, with a significant energy barrier separating the open and closed states.
authors.affiliation: Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Lewis
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Zachary M
authors.initials: ZM
authors.lastname: James
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Jesse E
authors.initials: JE
authors.lastname: McCaffrey
authors.affiliation: Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Braun
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Christine B
authors.initials: CB
authors.lastname: Karim
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota.
authors.forename: David D
authors.initials: DD
authors.lastname: Thomas
authors.affiliation: Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota. Electronic address: jnsachs@umn.edu.
authors.forename: Jonathan N
authors.initials: JN
authors.lastname: Sachs
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D006801:Humans; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000737:chemistry*
chemical_list: D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand