Structural Insights into mitochondrial antiviral signaling protein (MAVS)-tumor necrosis factor receptor-associated factor 6 (TRAF6) signaling

J Biol Chem. 2015 Oct 30;290(44):26811-20. doi: 10.1074/jbc.M115.666578. Epub 2015 Sep 18.


In response to viral infection, cytosolic retinoic acid-inducible gene I-like receptors sense viral RNA and promote oligomerization of mitochondrial antiviral signaling protein (MAVS), which then recruits tumor necrosis factor receptor-associated factor (TRAF) family proteins, including TRAF6, to activate an antiviral response. Currently, the interaction between MAVS and TRAF6 is only partially understood, and atomic details are lacking. Here, we demonstrated that MAVS directly interacts with TRAF6 through its potential TRAF6-binding motif 2 (T6BM2; amino acids 455-460). Further, we solved the crystal structure of MAVS T6BM2 in complex with the TRAF6 TRAF_C domain at 2.95 Å resolution. T6BM2 of MAVS binds to the canonical adaptor-binding groove of the TRAF_C domain. Structure-directed mutational analyses in vitro and in cells revealed that MAVS binding to TRAF6 via T6BM2 instead of T6BM1 is essential but not sufficient for an optimal antiviral response. Particularly, a MAVS mutant Y460E retained its TRAF6-binding ability as predicted but showed significantly impaired signaling activity, highlighting the functional importance of this tyrosine. Moreover, these observations were further confirmed in MAVS(-/-) mouse embryonic fibroblast cells. Collectively, our work provides a structural basis for understanding the MAVS-TRAF6 antiviral response.

Keywords: Antiviral signaling; MAVS; TNF receptor associated factor (TRAF); TRAF6; crystal structure; innate immunity; protein-protein interaction; signal transduction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / chemistry*
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Amino Acid Sequence
  • Animals
  • Crystallography, X-Ray
  • Escherichia coli / genetics
  • Escherichia coli / metabolism
  • Fibroblasts / metabolism*
  • Fibroblasts / virology
  • Gene Expression
  • Genes, Reporter
  • HEK293 Cells
  • Host-Pathogen Interactions / genetics*
  • Humans
  • Luciferases / genetics
  • Luciferases / metabolism
  • Mice
  • Mice, Knockout
  • Mitochondria / metabolism*
  • Mitochondria / virology
  • Molecular Sequence Data
  • Mutation
  • Protein Interaction Domains and Motifs
  • Protein Structure, Secondary
  • Recombinant Fusion Proteins / chemistry*
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Sendai virus / physiology
  • Sequence Alignment
  • Signal Transduction
  • TNF Receptor-Associated Factor 6 / chemistry*
  • TNF Receptor-Associated Factor 6 / genetics
  • TNF Receptor-Associated Factor 6 / metabolism


  • Adaptor Proteins, Signal Transducing
  • MAVS protein, human
  • Recombinant Fusion Proteins
  • TNF Receptor-Associated Factor 6
  • Luciferases

Associated data

  • PDB/1LB4
  • PDB/1LB5
  • PDB/1LB6