SYM-10-04: Queensland Protein Group Lecture

Structural basis of TIR domain assembly formation in MyD88-dependent TLR4 signaling

T Ve1,2, P Vajjhala1, A Hedger1, T Croll3, F Dimaio4, S Horsefield1, M Landsberg1,6, KJ Stacey1, EH Egelman5 and B Kobe1,6

  1. School of Chemistry and Molecular Biosciences, and Australian Infectious Diseases Research Centre, University of Queensland, Brisbane, QLD 4072, Australia
  2. Institute for Glycomics, Griffith University, Southport, QLD 4222, Australia
  3. School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD 4001, Australia
  4. Department of Biochemistry, University of Washington, Seattle, Washington, USA
  5. Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22908, USA
  6. Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, 4072, Australia

MyD88 and MAL are signaling mediators for the Toll-like receptor (TLR) family. MAL acts as a bridging adaptor between TLRs and MyD88, to form ternary complexes through Toll/interleukin-1 receptor (TIR) domain interactions. We found that MAL can either self-assemble or assemble with TLR4 TIR domain into filaments, and that MAL can induce formation of large MyD88 assemblies. A 7 Å resolution cryo-electron microscopy structure of the MAL filament reveals a tube of 12 proto-filaments that consists of two parallel strands of TIR domain subunits in a head-to-tail arrangement. The conserved BB-loop is critical for mediating head-to-tail interactions, and structure-guided mutagenesis, molecular modeling, and mapping of existing signaling mutations confirm that the proto-filament reproduces TIR domain interactions involved in TLR4 signaling. We propose that these interactions, representing TIR:TIR domain association modes in TLR/IL-1R signaling in general, are used to assemble open-ended TLR4:MAL:MyD88 complexes that enable Myddosome formation and IRAK kinase activation.