Oral Presentation Lorne Infection and Immunity 2018

Structural basis of signaling by cooperative assembly formation in innate immunity pathways (#22)

Thomas Ve 1 , Parimala R Vajjhala 2 , Andrew Hedger 2 , Tristan Croll 3 , Shane Horsefield 2 , Simon J Williams 4 , Michael J Landsberg 2 , Katryn J Stacey 2 , Edward H Egelman 5 , Bostjan Kobe 2
  1. Institute for Glycomics, Griffith University, Southport, QLD 4222, Australia
  2. School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, QLD 4072, Australia
  3. Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom
  4. Research School of Biology, The Australian National University, Canberra, ACT, Australia
  5. Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22908, USA

TIR (Toll/interleukin-1 receptor) domains are key components of innate immunity signaling pathways. They are found in animals, plants and bacteria, e.g. in TLRs (Toll-like receptors) and TLR adaptors in animals, NLRs (nucleotide binding, leucine-rich repeat receptors) in plants, and virulence factors interfering with immune responses in bacteria. While it is known that signaling depends on self-association and homotypic association of TIR domains, crystal structures have revealed few common association modes (1, 2). We have targeted TIR domains from mammals, bacteria, and plants, and have determined crystal structures for human TLR adaptor proteins MAL (3) and SARM (unpublished), the bacterial protein TcpB from Brucella melitensis (4) and the plant immune proteins L6 from flax (5), and RPS4, SNC1 and RPP1 (6,7), from Arabidopsis. These crystal structures have started revealing common trends in association modes, in particular for bacterial and plant TIR domains. Furthermore, for the TLR adaptors MAL and MyD88, we have been able to reconstitute large assemblies and we determined the structure for the filamentous assembly of MAL by cryo-electron microscopy [8]. Structure-guided mutagenesis, combined with in vivo interaction assays, demonstrated that the MAL interactions defined within the filament represent a template for a conserved mode of TIR-domain interaction involved in TLR signaling. Jointly, these studies suggest a general mechanism of function of TIR domains, which involves “signaling by cooperative assembly formation (SCAF)” with prion-like features that is consistent with signaling in other innate immunity pathways.

References:

1. Ve et al (2015) Apoptosis 20, 250, 2. Nimma et al (2017) Curr Opin Struct Biol 43, 122, 3. Valkov et al (2011) Proc Natl Acad Sci USA 108, 14879, 4. Alaidarous et al (2014) J Biol Chem 289, 654, 5. Bernoux et al (2011) Cell Host Microbe 9, 200, 6. Williams et al (2014) Science 344, 299, 7. Zhang et al (2017) Proc Natl Acad Sci USA 114, E2046, 8. Ve et al (2017) Nat Struct Mol Biol 24, 743.