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.
Original language | English (US) |
---|---|
Pages (from-to) | L21-L24 |
Journal | Biophysical journal |
Volume | 106 |
Issue number | 6 |
DOIs | |
State | Published - Mar 18 2014 |
Bibliographical note
Funding Information:Simulations were carried out using resources at the University of Minnesota Supercomputing Institute. Electron paramagnetic resonance experiments were performed at the Biophysical Spectroscopy Center, University of Minnesota. D.D.T. was supported by the National Institutes of Health grant No. GM27906.