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TitleThe NAD-mediated self-inhibition mechanism of pro-neurodegenerative SARM1.
Journal, issue, pagesNature, Vol. 588, Issue 7839, Page 658-663, Year 2020
Publish dateOct 14, 2020
AuthorsYuefeng Jiang / Tingting Liu / Chia-Hsueh Lee / Qing Chang / Jing Yang / Zhe Zhang /
PubMed AbstractPathological degeneration of axons disrupts neural circuits and represents one of the hallmarks of neurodegeneration. Sterile alpha and Toll/interleukin-1 receptor motif-containing protein 1 (SARM1) ...Pathological degeneration of axons disrupts neural circuits and represents one of the hallmarks of neurodegeneration. Sterile alpha and Toll/interleukin-1 receptor motif-containing protein 1 (SARM1) is a central regulator of this neurodegenerative process, and its Toll/interleukin-1 receptor (TIR) domain exerts its pro-neurodegenerative action through NADase activity. However, the mechanisms by which the activation of SARM1 is stringently controlled are unclear. Here we report the cryo-electron microscopy structures of full-length SARM1 proteins. We show that NAD is an unexpected ligand of the armadillo/heat repeat motifs (ARM) domain of SARM1. This binding of NAD to the ARM domain facilitated the inhibition of the TIR-domain NADase through the domain interface. Disruption of the NAD-binding site or the ARM-TIR interaction caused constitutive activation of SARM1 and thereby led to axonal degeneration. These findings suggest that NAD mediates self-inhibition of this central pro-neurodegenerative protein.
External linksNature / PubMed:33053563
MethodsEM (single particle)
Resolution2.6 - 3.0 Å
Structure data

EMDB-30401, PDB-7cm5:
Full-length Sarm1 in a self-inhibited state
Method: EM (single particle) / Resolution: 2.6 Å

EMDB-30402, PDB-7cm6:
NAD+-bound Sarm1 in the self-inhibited state
Method: EM (single particle) / Resolution: 3.0 Å

EMDB-30403, PDB-7cm7:
NAD+-bound Sarm1 E642A in the self-inhibited state
Method: EM (single particle) / Resolution: 2.6 Å

Chemicals

ChemComp-NAD:
NICOTINAMIDE-ADENINE-DINUCLEOTIDE / NAD*YM / Nicotinamide adenine dinucleotide

Source
  • homo sapiens (human)
KeywordsHYDROLASE / NADase / ARM / SAM / TIR

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