Modeling of tumor necrosis factor receptor superfamily 1A mutants associated with tumor necrosis factor receptor-associated periodic syndrome indicates misfolding consistent with abnormal function

Arthritis Rheum. 2006 Aug;54(8):2674-87. doi: 10.1002/art.21964.


Objective: To investigate the effect of mutations in the tumor necrosis factor receptor superfamily 1A (TNFRSF1A) gene on the conformation and behavior of the TNFRSF1A protein. Mutations in TNFRSF1A cause the autosomal-dominant, autoinflammatory TNFR-associated periodic syndrome (TRAPS).

Methods: The expression of recombinant TNFRSF1A was compared in SK-HEp-1 endothelial cells and HEK 293 epithelial cells stably transfected with full-length R347A or Deltasig constructs of wild-type or TRAPS-associated mutant TNFRSF1A. TNF binding was assessed in HEK 293 cell lines expressing R347A wild-type or mutant TNFRSF1A. Homology modeling of the 3-dimensional structure of the ectodomains of wild-type and mutant TNFRSF1A was performed.

Results: TRAPS-associated mutant and wild-type TNFRSF1A behaved differently and had different localization properties within the cell, as a direct result of mutations in the ectodomains of TNFRSF1A. From a structural perspective, mutants with a predicted structure similar to that of the wild-type protein (e.g., R92Q) behaved similarly to wild-type TNFRSF1A, whereas forms of TNFRSF1A with mutations predicted to drastically destabilize the protein structure (e.g., cysteine mutations) showed defects in cell surface expression and TNF binding.

Conclusion: The results obtained from the in vitro experiments, in combination with the modeled structures, indicate that the phenotype and clinical differences between different TRAPS-associated mutants of TNFRSF1A result from different conformations of the TNFRSF1A ectodomains.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology
  • Cell Line, Tumor
  • Epithelial Cells / cytology
  • Epithelial Cells / metabolism
  • Familial Mediterranean Fever / genetics*
  • Familial Mediterranean Fever / metabolism
  • Familial Mediterranean Fever / pathology
  • Humans
  • Kidney / cytology
  • Kidney / metabolism
  • Models, Molecular*
  • Mutation, Missense*
  • Protein Binding
  • Protein Conformation
  • Protein Folding
  • Receptors, Tumor Necrosis Factor, Type I / chemistry
  • Receptors, Tumor Necrosis Factor, Type I / genetics*
  • Receptors, Tumor Necrosis Factor, Type I / metabolism
  • Recombinant Fusion Proteins / metabolism
  • Tumor Necrosis Factor-alpha / metabolism


  • Receptors, Tumor Necrosis Factor, Type I
  • Recombinant Fusion Proteins
  • Tumor Necrosis Factor-alpha