An improved understanding of TNFL/TNFR interactions using structure-based classifications

Trends Biochem Sci. 2012 Sep;37(9):353-63. doi: 10.1016/j.tibs.2012.06.002. Epub 2012 Jul 11.


Tumor Necrosis Factor Ligand (TNFL)-Tumor Necrosis Factor Receptor (TNFR) interactions control key cellular processes; however, the molecular basis of the specificity of these interactions remains poorly understood. Using the T-RMSD (tree based on root mean square deviation), a newly developed structure-based sequence clustering method, we have re-analyzed the available structural data to re-interpret the interactions between TNFLs and TNFRs. This improves the classification of both TNFLs and TNFRs, such that the new groups defined here are in much stronger agreement with structural and functional features than existing schemes. Our clustering approach also identifies traces of a convergent evolutionary process for TNFLs and TNFRs, leading us to propose the co-evolution of TNFLs and the third cysteine rich domain (CRD) of large TNFRs.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Humans
  • Ligands
  • Phylogeny
  • Protein Interaction Domains and Motifs
  • Receptors, Tumor Necrosis Factor / chemistry*
  • Receptors, Tumor Necrosis Factor / genetics
  • Receptors, Tumor Necrosis Factor / metabolism
  • Tumor Necrosis Factors / chemistry*
  • Tumor Necrosis Factors / metabolism


  • Ligands
  • Receptors, Tumor Necrosis Factor
  • Tumor Necrosis Factors