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TitleSARM1 is a metabolic sensor activated by an increased NMN/NAD ratio to trigger axon degeneration.
Journal, issue, pagesNeuron, Vol. 109, Issue 7, Page 1118-1136.e11, Year 2021
Publish dateApr 7, 2021
AuthorsMatthew D Figley / Weixi Gu / Jeffrey D Nanson / Yun Shi / Yo Sasaki / Katie Cunnea / Alpeshkumar K Malde / Xinying Jia / Zhenyao Luo / Forhad K Saikot / Tamim Mosaiab / Veronika Masic / Stephanie Holt / Lauren Hartley-Tassell / Helen Y McGuinness / Mohammad K Manik / Todd Bosanac / Michael J Landsberg / Philip S Kerry / Mehdi Mobli / Robert O Hughes / Jeffrey Milbrandt / Bostjan Kobe / Aaron DiAntonio / Thomas Ve /
PubMed AbstractAxon degeneration is a central pathological feature of many neurodegenerative diseases. Sterile alpha and Toll/interleukin-1 receptor motif-containing 1 (SARM1) is a nicotinamide adenine dinucleotide ...Axon degeneration is a central pathological feature of many neurodegenerative diseases. Sterile alpha and Toll/interleukin-1 receptor motif-containing 1 (SARM1) is a nicotinamide adenine dinucleotide (NAD)-cleaving enzyme whose activation triggers axon destruction. Loss of the biosynthetic enzyme NMNAT2, which converts nicotinamide mononucleotide (NMN) to NAD, activates SARM1 via an unknown mechanism. Using structural, biochemical, biophysical, and cellular assays, we demonstrate that SARM1 is activated by an increase in the ratio of NMN to NAD and show that both metabolites compete for binding to the auto-inhibitory N-terminal armadillo repeat (ARM) domain of SARM1. We report structures of the SARM1 ARM domain bound to NMN and of the homo-octameric SARM1 complex in the absence of ligands. We show that NMN influences the structure of SARM1 and demonstrate via mutagenesis that NMN binding is required for injury-induced SARM1 activation and axon destruction. Hence, SARM1 is a metabolic sensor responding to an increased NMN/NAD ratio by cleaving residual NAD, thereby inducing feedforward metabolic catastrophe and axonal demise.
External linksNeuron / PubMed:33657413 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution1.65 - 3.35 Å
Structure data

23278

7ld0

EMDB-23278, PDB-7ld0:
Cryo-EM structure of ligand-free Human SARM1
Method: EM (single particle) / Resolution: 3.1 Å

PDB-7lcy:
Crystal structure of the ligand-free ARM domain from Drosophila SARM1
Method: X-RAY DIFFRACTION / Resolution: 3.35 Å

PDB-7lcz:
Crystal structure of the ARM domain from Drosophila SARM1 in complex with NMN
Method: X-RAY DIFFRACTION / Resolution: 1.65 Å

Chemicals

ChemComp-NMN:
BETA-NICOTINAMIDE RIBOSE MONOPHOSPHATE

ChemComp-EDO:
1,2-ETHANEDIOL

ChemComp-NA:
Unknown entry

ChemComp-HOH:
WATER

Source
  • homo sapiens (human)
  • drosophila melanogaster (fruit fly)
KeywordsHYDROLASE / NADase / Autoinhibition / ARM domain / Allostery / SIGNALING PROTEIN / Neurodegeneration / NAD / Toxin

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