|Entry||Database: PDB / ID: 7cm6|
|Title||NAD+-bound Sarm1 in the self-inhibited state|
|Components||NAD(+) hydrolase SARM1|
|Keywords||HYDROLASE / NADase / ARM / SAM / TIR|
|Function / homology|
Function and homology information
negative regulation of MyD88-independent toll-like receptor signaling pathway / Toll Like Receptor 3 (TLR3) Cascade / MyD88-independent TLR4 cascade / NAD catabolic process / NAD+ nucleosidase activity / ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase / NAD+ nucleotidase, cyclic ADP-ribose generating / NAD(P)+ nucleosidase activity / Hydrolases; Glycosylases; Hydrolysing N-glycosyl compounds / signaling adaptor activity ...negative regulation of MyD88-independent toll-like receptor signaling pathway / Toll Like Receptor 3 (TLR3) Cascade / MyD88-independent TLR4 cascade / NAD catabolic process / NAD+ nucleosidase activity / ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase / NAD+ nucleotidase, cyclic ADP-ribose generating / NAD(P)+ nucleosidase activity / Hydrolases; Glycosylases; Hydrolysing N-glycosyl compounds / signaling adaptor activity / regulation of dendrite morphogenesis / regulation of neuron apoptotic process / extrinsic component of mitochondrial outer membrane / response to axon injury / regulation of neuron death / response to glucose / TRAF6-mediated induction of TAK1 complex within TLR4 complex / Activation of IRF3/IRF7 mediated by TBK1/IKK epsilon / IKK complex recruitment mediated by RIP1 / positive regulation of neuron death / nervous system development / microtubule / anchoring junction / cell differentiation / axon / synapse / dendrite / innate immune response / signal transduction / mitochondrion / identical protein binding / cytosol / cytoplasm
Similarity search - Function
Sterile alpha and TIR motif-containing protein 1 / TIR domain / Toll - interleukin 1 - resistance / TIR domain profile. / Toll/interleukin-1 receptor homology (TIR) domain / Toll/interleukin-1 receptor homology (TIR) domain superfamily / SAM domain (Sterile alpha motif) / SAM domain profile. / Sterile alpha motif. / Sterile alpha motif domain ...Sterile alpha and TIR motif-containing protein 1 / TIR domain / Toll - interleukin 1 - resistance / TIR domain profile. / Toll/interleukin-1 receptor homology (TIR) domain / Toll/interleukin-1 receptor homology (TIR) domain superfamily / SAM domain (Sterile alpha motif) / SAM domain profile. / Sterile alpha motif. / Sterile alpha motif domain / Sterile alpha motif/pointed domain superfamily / Armadillo-like helical / Armadillo-type fold
Similarity search - Domain/homology
NICOTINAMIDE-ADENINE-DINUCLEOTIDE / NAD(+) hydrolase SARM1
Similarity search - Component
|Biological species||Homo sapiens (human)|
|Method||ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3 Å|
|Authors||Zhang, Z. / Jiang, Y.|
|Citation||Journal: Nature / Year: 2020|
Title: The NAD-mediated self-inhibition mechanism of pro-neurodegenerative SARM1.
Authors: Yuefeng Jiang / Tingting Liu / Chia-Hsueh Lee / Qing Chang / Jing Yang / Zhe Zhang /
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.
|Structure viewer||Molecule: |
Downloads & links
A: NAD(+) hydrolase SARM1
B: NAD(+) hydrolase SARM1
C: NAD(+) hydrolase SARM1
D: NAD(+) hydrolase SARM1
E: NAD(+) hydrolase SARM1
F: NAD(+) hydrolase SARM1
G: NAD(+) hydrolase SARM1
H: NAD(+) hydrolase SARM1
Mass: 80504.289 Da / Num. of mol.: 8
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SARM1, KIAA0524, SAMD2, SARM / Production host: Homo sapiens (human)
References: UniProt: Q6SZW1, ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase, Hydrolases; Glycosylases; Hydrolysing N-glycosyl compounds
Mass: 663.425 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C21H27N7O14P2 / Feature type: SUBJECT OF INVESTIGATION / Comment: NAD*YM
|Has ligand of interest||Y|
|Experiment||Method: ELECTRON MICROSCOPY|
|EM experiment||Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction|
|Component||Name: Octamer of full-length Sarm1 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT|
|Molecular weight||Value: 640 kDa/nm / Experimental value: YES|
|Source (natural)||Organism: Homo sapiens (human)|
|Source (recombinant)||Organism: Homo sapiens (human)|
|Buffer solution||pH: 8|
|Specimen||Conc.: 3 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES|
|Specimen support||Grid material: GOLD / Grid mesh size: 400 divisions/in. / Grid type: Quantifoil R1.2/1.3|
|Vitrification||Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 283 K|
-Electron microscopy imaging
Model: Titan Krios / Image courtesy: FEI Company
|Microscopy||Model: FEI TITAN KRIOS|
|Electron gun||Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM|
|Electron lens||Mode: BRIGHT FIELDBright-field microscopy|
|Image recording||Electron dose: 57.5 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)|
|CTF correction||Type: NONE|
|Particle selection||Num. of particles selected: 466398|
|3D reconstruction||Resolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 57708 / Symmetry type: POINT|
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