Poster Presentation The 46th Lorne Conference on Protein Structure and Function 2021

Understanding the molecular pathway of SARM1 regulation (#404)

Forhad K Saikot 1 , Weixi Gu 1 , Mohammad Manik 1 , Yun Shi 2 , Thomas Ve 3 , Jeff D Nanson 1 , Bostjan Kobe 1
  1. School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD, Australia
  2. Institute for Glycomics, Griffith University, Southport, QLD, Australia
  3. Institute for Glycomics, Griffith University, Southport, Qld, Australia

Numerous evidences suggest the prevalence of axonal degeneration (AxD) prior to onset of many neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease and amyotrophic lateral sclerosis. Wallerian degeneration (WD) is an anciently noted pattern of AxD that follows injury or chemical insult. At molecular level, WD is regulated by the action of a novel protein called sterile alpha and Toll/interleukin receptor (TIR) motif-containing 1 (SARM1). SARM1 contains an ARM domain, two tandem SAM domains and a TIR domain. Previous structural and functional data revealed the NADase activity of TIR domain, which is facilitated by the octameric SAM domain. Loss of NAD+ due to activation of SARM1 is the main culprit in AxD. Recent structural data showed how ARM domain disintegrates TIR self-interaction and thus, maintains autoinhibition. The ARM domain can interact with both NAD+ and NMN, a precursor of NAD+. These two molecules play a crucial role as the molecular switch of SARM1. This mechanism is conserved through different organisms; however, quite elusive so far. To understand the whole pathway, it is essential to determine the active conformation of SARM1. This project aims to solve the 3D structure of the activated protein and to understand how the catalytic activity is regulated at molecular level.

  1. Horsefield, S., et al., NAD+ cleavage activity by animal and plant TIR domains in cell death pathways. Science, 2019. 365(6455): p. 793-799.
  2. Essuman, K., et al., TIR domain proteins are an ancient family of NAD+-consuming enzymes. Current Biology, 2018. 28(3): p. 421-430. e4.
  3. Sporny, M., et al., Structural evidence for an octameric ring arrangement of SARM1. Journal of Molecular Biology, 2019. 431(19): p. 3591-3605.
  4. Jiang, Y., et al., The NAD+-mediated self-inhibition mechanism of pro-neurodegenerative SARM1. Nature, 2020. 588: p. 658–663.