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| Title | The NAD-mediated self-inhibition mechanism of pro-neurodegenerative SARM1. |
|---|---|
| Journal, issue, pages | Nature, Vol. 588, Issue 7839, Page 658-663, Year 2020 |
| Publish date | Oct 14, 2020 |
 Authors | Yuefeng Jiang / Tingting Liu / Chia-Hsueh Lee / Qing Chang / Jing Yang / Zhe Zhang /   |
| PubMed Abstract | 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) ...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 links | Nature / PubMed:33053563 |
| Methods | EM (single particle) |
| Resolution | 2.6 - 3.0 Å |
| Structure data | EMDB-30401, PDB-7cm5: EMDB-30402, PDB-7cm6: EMDB-30403, PDB-7cm7: |
| Chemicals |  ChemComp-NAD: |
| Source |
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 Keywords | HYDROLASE / NADase / ARM / SAM / TIR |
homo sapiens (human)
