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- EMDB-11191: SARM1 SAM1-2 domains -

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Basic information

Entry
Database: EMDB / ID: EMD-11191
TitleSARM1 SAM1-2 domains
Map data
Sample
  • Complex: hSARM1
    • Protein or peptide: Sterile alpha and TIR motif-containing protein 1
  • Ligand: 1,2-ETHANEDIOL
  • Ligand: BETA-MERCAPTOETHANOL
  • Ligand: DI(HYDROXYETHYL)ETHER
  • Ligand: TRIETHYLENE GLYCOL
KeywordsNADase / SAM domain / HYDROLASE
Function / homology
Function and homology information


extrinsic component of synaptic membrane / negative regulation of MyD88-independent toll-like receptor signaling pathway / MyD88-independent TLR4 cascade / NADP+ nucleosidase activity / Toll Like Receptor 3 (TLR3) Cascade / NAD+ catabolic process / NAD+ nucleosidase activity / regulation of synapse pruning / modification of postsynaptic structure / ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase ...extrinsic component of synaptic membrane / negative regulation of MyD88-independent toll-like receptor signaling pathway / MyD88-independent TLR4 cascade / NADP+ nucleosidase activity / Toll Like Receptor 3 (TLR3) Cascade / NAD+ catabolic process / NAD+ nucleosidase activity / regulation of synapse pruning / modification of postsynaptic structure / ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase / protein localization to mitochondrion / NAD+ nucleosidase activity, cyclic ADP-ribose generating / nervous system process / Hydrolases; Glycosylases; Hydrolysing N-glycosyl compounds / regulation of dendrite morphogenesis / response to glucose / response to axon injury / regulation of neuron apoptotic process / signaling adaptor activity / TRAF6-mediated induction of TAK1 complex within TLR4 complex / Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE) / IKK complex recruitment mediated by RIP1 / neuromuscular junction / nervous system development / microtubule / mitochondrial outer membrane / cell differentiation / axon / innate immune response / dendrite / synapse / glutamatergic synapse / cell surface / signal transduction / protein-containing complex / mitochondrion / identical protein binding / cytoplasm / cytosol
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
NAD(+) hydrolase SARM1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.77 Å
AuthorsSporny M / Guez-Haddad J
Funding support Israel, 2 items
OrganizationGrant numberCountry
Israel Science Foundation1425/15 Israel
Israel Science Foundation909/19 Israel
CitationJournal: Elife / Year: 2020
Title: Structural basis for SARM1 inhibition and activation under energetic stress.
Authors: Michael Sporny / Julia Guez-Haddad / Tami Khazma / Avraham Yaron / Moshe Dessau / Yoel Shkolnisky / Carsten Mim / Michail N Isupov / Ran Zalk / Michael Hons / Yarden Opatowsky /
Abstract: SARM1, an executor of axonal degeneration, displays NADase activity that depletes the key cellular metabolite, NAD+, in response to nerve injury. The basis of SARM1 inhibition and its activation ...SARM1, an executor of axonal degeneration, displays NADase activity that depletes the key cellular metabolite, NAD+, in response to nerve injury. The basis of SARM1 inhibition and its activation under stress conditions are still unknown. Here, we present cryo-EM maps of SARM1 at 2.9 and 2.7 Å resolutions. These indicate that SARM1 homo-octamer avoids premature activation by assuming a packed conformation, with ordered inner and peripheral rings, that prevents dimerization and activation of the catalytic domains. This inactive conformation is stabilized by binding of SARM1's own substrate NAD+ in an allosteric location, away from the catalytic sites. This model was validated by mutagenesis of the allosteric site, which led to constitutively active SARM1. We propose that the reduction of cellular NAD+ concentration contributes to the disassembly of SARM1's peripheral ring, which allows formation of active NADase domain dimers, thereby further depleting NAD+ to cause an energetic catastrophe and cell death.
History
DepositionJun 18, 2020-
Header (metadata) releaseNov 11, 2020-
Map releaseNov 11, 2020-
UpdateApr 9, 2025-
Current statusApr 9, 2025Processing site: PDBe / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.18
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.18
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6zg1
  • Surface level: 0.18
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_11191.png

Downloads & links

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Map

FileDownload / File: emd_11191.map.gz / Format: CCP4 / Size: 12.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.1 Å/pix.
x 150 pix.
= 165. Å		1.1 Å/pix.
x 150 pix.
= 165. Å		1.1 Å/pix.
x 150 pix.
= 165. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.1 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.18 / Movie #1: 0.18
Minimum - Maximum-0.30336773 - 0.593314
Average (Standard dev.)0.00280802 (±0.037363835)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions150150150
Spacing150150150
CellA=B=C: 165.0 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.11.11.1
M x/y/z150150150
origin x/y/z0.0000.0000.000
length x/y/z165.000165.000165.000
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ240240240
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS150150150
D min/max/mean-0.3030.5930.003

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Supplemental data

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Sample components

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Entire : hSARM1

EntireName: hSARM1
Components
  • Complex: hSARM1
    • Protein or peptide: Sterile alpha and TIR motif-containing protein 1
  • Ligand: 1,2-ETHANEDIOL
  • Ligand: BETA-MERCAPTOETHANOL
  • Ligand: DI(HYDROXYETHYL)ETHER
  • Ligand: TRIETHYLENE GLYCOL

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Supramolecule #1: hSARM1

SupramoleculeName: hSARM1 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Sterile alpha and TIR motif-containing protein 1

MacromoleculeName: Sterile alpha and TIR motif-containing protein 1 / type: protein_or_peptide / ID: 1 / Number of copies: 8 / Enantiomer: LEVO / EC number: ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 18.823461 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
GSSALAKRAL RLLGEEVPRP ILPSVPSWKE AEVQTWLQQI GFSKYCESFR EQQVDGDLLL RLTEEELQTD LGMKSGITRK RFFRELTEL KTFANYSTCD RSNLADWLGS LDPRFRQYTY GLVSCGLDRS LLHRVSEQQL LEDCGIHLGV HRARILTAAR E MLHS

UniProtKB: NAD(+) hydrolase SARM1

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Macromolecule #2: 1,2-ETHANEDIOL

MacromoleculeName: 1,2-ETHANEDIOL / type: ligand / ID: 2 / Number of copies: 17 / Formula: EDO
Molecular weightTheoretical: 62.068 Da
Chemical component information

ChemComp-EDO:
1,2-ETHANEDIOL

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Macromolecule #3: BETA-MERCAPTOETHANOL

MacromoleculeName: BETA-MERCAPTOETHANOL / type: ligand / ID: 3 / Number of copies: 8 / Formula: BME
Molecular weightTheoretical: 78.133 Da
Chemical component information

ChemComp-BME:
BETA-MERCAPTOETHANOL

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Macromolecule #4: DI(HYDROXYETHYL)ETHER

MacromoleculeName: DI(HYDROXYETHYL)ETHER / type: ligand / ID: 4 / Number of copies: 2 / Formula: PEG
Molecular weightTheoretical: 106.12 Da
Chemical component information

ChemComp-PEG:
DI(HYDROXYETHYL)ETHER

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Macromolecule #5: TRIETHYLENE GLYCOL

MacromoleculeName: TRIETHYLENE GLYCOL / type: ligand / ID: 5 / Number of copies: 1 / Formula: PGE
Molecular weightTheoretical: 150.173 Da
Chemical component information

ChemComp-PGE:
TRIETHYLENE GLYCOL

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI POLARA 300
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Average electron dose: 80.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Tecnai Polara / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.77 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 43868
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: MAXIMUM LIKELIHOOD

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