TNFR1 signaling is associated with backbone conformational changes of receptor dimers consistent with overactivation in the R92Q TRAPS mutant

Biochemistry. 2012 Aug 21;51(33):6545-55. doi: 10.1021/bi3006626. Epub 2012 Aug 8.


The widely accepted model for tumor necrosis factor 1 (TNFR1) signaling is that ligand binding causes receptor trimerization, which triggers a reorganization of cytosolic domains and thus initiates intracellular signaling. This model of stoichiometrically driven receptor activation does not account for the occurrence of ligand independent signaling in overexpressed systems, nor does it explain the constitutive activity of the R92Q mutant associated with TRAPS. More recently, ligand binding has been shown to result in the formation of high molecular weight, oligomeric networks. Although the dimer, shown to be the preligand structure, is thought to remain present within ligand-receptor networks, it is unknown whether network formation or ligand-induced structural change to the dimer itself is the trigger for TNFR1 signaling. In the present study, we investigate the available crystal structures of TNFR1 to explore backbone dynamics and infer conformational transitions associated with ligand binding. Using normal-mode analysis, we characterize the dynamic coupling between the TNFR1 ligand binding and membrane proximal domains and suggest a mechanism for ligand-induced activation. Furthermore, our data are supported experimentally by FRET showing that the constitutively active R92Q mutant adopts an altered conformation compared to wild-type. Collectively, our results suggest that the signaling competent architecture is the receptor dimer and that ligand binding modifies domain mobilities intrinsic to the receptor structure, allowing it to sample a separate, active conformation mediated by network formation.

MeSH terms

  • Fever
  • Fluorescence Resonance Energy Transfer
  • HEK293 Cells
  • Hereditary Autoinflammatory Diseases / genetics
  • Hereditary Autoinflammatory Diseases / physiopathology*
  • Humans
  • Ligands
  • Models, Molecular
  • Point Mutation
  • Protein Binding
  • Protein Conformation / drug effects
  • Protein Multimerization
  • Protein Structure, Tertiary
  • Receptors, Tumor Necrosis Factor, Type I / genetics
  • Receptors, Tumor Necrosis Factor, Type I / physiology*
  • Signal Transduction / physiology*


  • Ligands
  • Receptors, Tumor Necrosis Factor, Type I

Supplementary concepts

  • Periodic fever, familial, autosomal dominant