7CM7

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

Summary for 7CM7

• Entry DOI: 10.2210/pdb7cm7/pdb
• EMDB information: 30403
• Descriptor: NAD(+) hydrolase SARM1, NICOTINAMIDE-ADENINE-DINUCLEOTIDE (2 entities in total)
• Functional Keywords: nadase, arm, sam, tir, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 8
• Total formula weight: 648877.40

Authors

Zhang, Z.,Jiang, Y. (deposition date: 2020-07-25, release date: 2020-10-21, Last modification date: 2024-03-27)

Primary citation

Jiang, 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

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

Experimental method

ELECTRON MICROSCOPY (2.6 Å)