Poster Presentation The 47th Lorne Conference on Protein Structure and Function 2022

Allosteric regulation of SARM1, the executioner of axon degeneration (#344)

Weixi Gu 1 , Zhenyao Luo 1 , Thomas Ve 2 , Jeffrey D Nanson 1 , Bostjan Kobe 1
  1. School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, QLD, Australia
  2. Institute for Glycomics, Griffith University, Southport, QLD, Australia

Programmed axon degeneration is a subcellular self-destruction program that can be activated in genetic, toxic and metabolic disorders, as well as physical injury, leading to the axon pathology. The central executioner of this process is SARM1, a TIR (Toll/interleukin-1 receptor) domain-containing protein with NADase, NADPase and base-exchange activities, whose activation is regulated by its ARM (armadillo repeat motif) domain, by sensing the changes of the NMN (nicotinamide mononucleotide)/NAD (nicotinamide adenine dinucleotide) ratio in axons1. We sought to understand this allosteric regulation of SARM1 by crystallographic analysis of Drosophila SARM1 ARM domain (dSARM1ARM).

We previously determined the crystal structure of NMN-bound dSARM1ARM using MIRAS phasing2,3. By comparing this structure with ligand-free dSARM1ARM, we first showed that the primary activator NMN binds to SARM1 allosteric site and induces a compaction of the ARM domain2. VMN (vacor mononucleotide), a metabolite of neurotoxin vacor, is an even more potent activator of the protein than NMN4. The crystal structure of VMN-bound dSARM1ARM adopts a similar conformation to the NMN-bound structure, with VMN showing a similar binding mode to NMN, but making even more contacts with the protein4. NaMN (nicotinic acid mononucleotide), a biosynthetic precursor of NAD, on the other hand, acts as an inhibitor of the protein. NaMN binds to the same allosteric site, but stabilises a more extended conformation, similar to the ligand-free dSARM1ARM, representing the inactive state of the protein5. Our results illustrate that the conformational changes in the ARM domain play a role in the allosteric regulation of SARM1 and will provide valuable information for developing anti-SARM1 drugs for a range of neurodegenerative diseases.

 

  1. Hopkins, E. L*., Gu, W*., Kobe, B. & Coleman, M. P. (2021). A Novel NAD Signaling Mechanism in Axon Degeneration and its Relationship to Innate Immunity. Front Mol Biosci. 8:703532. doi: 10.3389/fmolb.2021.703532.
  2. Figley, M*., Gu, W*., Nanson, J. D*., Shi, Y*., Sasaki, Y., Cunnea, K., Malde, A. K., Jia, X., Luo, Z., Saiko, F. K., Mosaiab, T., Masic, V., Holt, S., Hartley-Tassell, L., McGuinness, H. Y., Manik, M. K., Bosanac, T., Landsberg, M. J., Kerry, P. S., Mobli, M., Hughes, R. O., Milbrandt, J., Kobe, B., DiAntonio, A. & Ve, T. (2021). SARM1 is a metabolic sensor activated by an increased NMN/NAD(+) ratio to trigger axon degeneration. Neuron. 109(7), 1118-1136. doi: 10.1016/j.neuron.2021.02.009.
  3. Gu, W*., Luo, Z*., Vonrheine, C., Jia, X., Ve, T., Nanson, J. D. & Kobe, B. (2021). Crystal structure determination of the armadillo repeat motif (ARM) domain from Drosophila SARM1 using MIRAS phasing. Acta Crystallogr F Struct Biol Commun, 77(10). doi: 10.1107/S2053230X21006786.
  4. Loreto, A., Angeletti, C., Gu, W., Osborne, A, Nieuwenhuis, B., Gilley, J., Arthur-Farraj, P., Merlini, E., Amici, A., Luo, Z., Hartley-Tassell, L., Ve, T., Desrochers, L. M., Wang, Q., Kobe, B., Orsomando, G. & Coleman, M. P. (2021). Potent activation of the programmed axon death pathway regulator SARM1 underlies neurotoxicity by vacor. eLife, revision to be submitted.
  5. Sasaki, Y., Zhu, J., Shi, Y., Gu, W., Kobe, B., Ve, T., DiAntonio, A. & Milbrandt, J. (2021). Nicotinic acid mononucleotide is an allosteric SARM1 inhibitor promoting axonal protection. Exp. Neurol. 345:113842. doi: 10.1016/j.expneurol.2021.113842.