EMD-30403

Single-particle
2.6 Å
EMD-30403 Deposition: 25/07/2020
Map released: 21/10/2020
Last modified: 27/03/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links

EMD-30403

NAD+-bound Sarm1 E642A in the self-inhibited state

EMD-30403

Single-particle
2.6 Å
EMD-30403 Deposition: 25/07/2020
Map released: 21/10/2020
Last modified: 27/03/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Sample Organism: Homo sapiens
Sample: Octamer of full-length Sarm1 E642A
Fitted models: 7cm7 (Avg. Q-score: 0.476)

Deposition Authors: Zhang Z , Jiang Y
The NAD + -mediated self-inhibition mechanism of pro-neurodegenerative SARM1.
Jiang Y , Liu T, Lee CH, Chang Q , Yang J , Zhang Z
(2020) Nature , 588 , 658 - 663
PUBMED: 33053563
DOI: doi:10.1038/s41586-020-2862-z
ISSN: 1476-4687
ASTM: NATUAS
Abstract:
Pathological degeneration of axons disrupts neural circuits and represents one of the hallmarks of neurodegeneration1-4. Sterile alpha and Toll/interleukin-1 receptor motif-containing protein 1 (SARM1) is a central regulator of this neurodegenerative process5-8, and its Toll/interleukin-1 receptor (TIR) domain exerts its pro-neurodegenerative action through NADase activity9,10. 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.