Poster Presentation The 42nd Lorne Conference on Protein Structure and Function 2017

Structural and biochemical characterisation of SARM in axon degeneration and cell death (#154)

Shane Horsefield 1 , Thomas Ve 1 2 , Xiaoxiao Zhang 3 , Lachlan Casey 1 , Bostjan Kobe 1 4
  1. The University of Queensland, St. Lucia, QLD, Australia
  2. Institute for Glycomics, Griffith University, Southport, QLD, Australia
  3. Commonwealth Scientific and Industrial Research Organisation, CSIRO, Canberra, ACT, Australia
  4. Institute for Molecular Biosciences, The University of Queensland, Brisbane, QLD, Australia

Degeneration of axons eliminates unwanted or damaged nerves from an organism as part of normal neuronal development and injury, but is also a common feature in neurodegenerative disease and neuropathies. Recently, a Toll-like receptor (TLR) adaptor protein, sterile-alpha and armadillo motif-containing protein (SARM), has shown to promote axon degeneration after injury (Wallerian degeneration). The SARM protein also inhibits TLR signalling and promotes cell death. The protein comprises three domains: two central tandem sterile-alpha motifs (SAM) flanked by an N-terminal armadillo repeat motif (ARM) and a C-terminal Toll/interleukin-1 receptor (TIR) domain. We have solved the crystal structure of the tandem SAM domains of human SARM at 2.8 Å resolution which form an octameric ring. Using small-angle X-ray scattering (SAXS) and multi-angle light scattering (MALS) we can determine this ring structure is conserved across species. TIR domains are responsible for transmitting signal in TLR signalling and requires a clustering event to bring TIR domains in close proximity. We have solved the crystal structure of the TIR domain of human SARM at 1.8 Å resolution. In relation to SARM promoting axon degeneration and cell-death, we hypothesise that the tandem SAM domains act as the "clustering mechanism" to bring the TIR domains together. We are currently testing mutants that knock out the oligomeric ring to confirm whether this prevents axon degeneration and cell-death. We also are investigating the function of the TIR domain, based on our solved crystal structure, which could provide new targets for therapeutic drugs in neurodegenerative disease and neuropathies. This concept of forming complex assemblies in immunity and inflammation are seen in other immune pathways, such as the inflammasome pathway, effector-triggered immunity in plants and apoptosis.

  1. Gay, N.J., and Gangloff, M. (2007). Structure and function of Toll receptors and their ligands. Annual review of biochemistry 76, 141-165.
  2. Kawai, T., and Akira, S. (2010). The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nature immunology 11, 373-384.
  3. O'Neill, L.A., Golenbock, D., and Bowie, A.G. (2013). The history of Toll-like receptors - redefining innate immunity. Nature reviews. Immunology 13, 453-460.
  4. Ve, T., Gay, N.J., Mansell, A., Kobe, B., and Kellie, S. (2012). Adaptors in toll-like receptor signaling and their potential as therapeutic targets. Current drug targets 13, 1360-1374.