7CM5
Full-length Sarm1 in a self-inhibited state
Summary for 7CM5
Entry DOI | 10.2210/pdb7cm5/pdb |
EMDB information | 30401 |
Descriptor | NAD(+) hydrolase SARM1 (1 entity in total) |
Functional Keywords | nadase, arm, sam, tir, hydrolase |
Biological source | Homo sapiens (Human) |
Total number of polymer chains | 8 |
Total formula weight | 644034.31 |
Authors | |
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 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: 33053563DOI: 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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