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7CM5

Full-length Sarm1 in a self-inhibited state

Summary for 7CM5
Entry DOI10.2210/pdb7cm5/pdb
EMDB information30401
DescriptorNAD(+) hydrolase SARM1 (1 entity in total)
Functional Keywordsnadase, arm, sam, tir, hydrolase
Biological sourceHomo sapiens (Human)
Total number of polymer chains8
Total formula weight644034.31
Authors
Zhang, Z.,Jiang, Y. (deposition date: 2020-07-24, release date: 2020-10-21, Last modification date: 2024-03-27)
Primary citationJiang, Y.,Liu, T.,Lee, C.H.,Chang, Q.,Yang, J.,Zhang, Z.
The NAD + -mediated self-inhibition mechanism of pro-neurodegenerative SARM1.
Nature, 588:658-663, 2020
Cited by
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) 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.
PubMed: 33053563
DOI: 10.1038/s41586-020-2862-z
PDB entries with the same primary citation
Experimental method
ELECTRON MICROSCOPY (2.6 Å)
Structure validation

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