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- EMDB-11187: hSARM1 GraFix-ed -

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Basic information

Entry
Database: EMDB / ID: EMD-11187
TitlehSARM1 GraFix-ed
Map data
SamplehSARM1:
NAD(+) hydrolase SARM1 / ligand
Function / homology
Function and homology information


extrinsic component of mitochondrial outer membrane / NAD catabolic process / negative regulation of MyD88-independent toll-like receptor signaling pathway / NAD+ nucleosidase activity / Hydrolases; Glycosylases; Hydrolysing N-glycosyl compounds / NAD+ nucleotidase, cyclic ADP-ribose generating / ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase / NAD(P)+ nucleosidase activity / signaling adaptor activity / regulation of dendrite morphogenesis ...extrinsic component of mitochondrial outer membrane / NAD catabolic process / negative regulation of MyD88-independent toll-like receptor signaling pathway / NAD+ nucleosidase activity / Hydrolases; Glycosylases; Hydrolysing N-glycosyl compounds / NAD+ nucleotidase, cyclic ADP-ribose generating / ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase / NAD(P)+ nucleosidase activity / signaling adaptor activity / regulation of dendrite morphogenesis / regulation of neuron death / response to axon injury / response to glucose / positive regulation of neuron death / microtubule / regulation of apoptotic process / synapse / axon / dendrite / innate immune response / signal transduction / mitochondrion / identical protein binding / cytosol / cytoplasm
Sterile alpha motif domain / Sterile alpha and TIR motif-containing protein 1 / Toll/interleukin-1 receptor homology (TIR) domain superfamily / Armadillo-type fold / Toll/interleukin-1 receptor homology (TIR) domain / Sterile alpha motif/pointed domain superfamily / Armadillo-like helical
NAD(+) hydrolase SARM1
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.88 Å
AuthorsSporny M / Guez-Haddad J / Khazma T / Yaron A / Dessau M / Mim C / Isupov MN / Zalk R / Hons M / Opatowsky Y
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.
Validation ReportPDB-ID: 6zfx

SummaryFull reportAbout validation report
History
DepositionJun 18, 2020-
Header (metadata) releaseNov 18, 2020-
Map releaseNov 18, 2020-
UpdateNov 25, 2020-
Current statusNov 25, 2020Processing site: PDBe / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.1
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.1
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6zfx
  • Surface level: 0.1
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

Downloads & links

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Map

FileDownload / File: emd_11187.map.gz / Format: CCP4 / Size: 163.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 350 pix.
= 289.45 Å
0.83 Å/pix.
x 350 pix.
= 289.45 Å
0.83 Å/pix.
x 350 pix.
= 289.45 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.827 Å
Density
Contour LevelBy AUTHOR: 0.1 / Movie #1: 0.1
Minimum - Maximum-0.21308525 - 0.6449051
Average (Standard dev.)0.0020778992 (±0.023871161)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions350350350
Spacing350350350
CellA=B=C: 289.45 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.8270.8270.827
M x/y/z350350350
origin x/y/z0.0000.0000.000
length x/y/z289.450289.450289.450
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS350350350
D min/max/mean-0.2130.6450.002

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Supplemental data

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Sample components

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Entire hSARM1

EntireName: hSARM1 / Number of components: 3

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Component #1: protein, hSARM1

ProteinName: hSARM1 / Recombinant expression: No
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Homo sapiens (human) / Cell of expression system: HEK293F

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Component #2: protein, NAD(+) hydrolase SARM1

ProteinName: NAD(+) hydrolase SARM1 / Number of Copies: 8 / Recombinant expression: No
MassTheoretical: 79.971258 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Homo sapiens (human)

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Component #3: ligand, (~{E})-4-methylnon-4-enedial

LigandName: (~{E})-4-methylnon-4-enedial / Number of Copies: 16 / Recombinant expression: No
MassTheoretical: 0.168233 kDa

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Experimental details

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Sample preparation

SpecimenSpecimen state: Particle / Method: cryo EM
Sample solutionpH: 8.8
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
ImagingMicroscope: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Electron dose: 50 e/Å2 / Illumination mode: FLOOD BEAM
LensImaging mode: BRIGHT FIELD
Specimen HolderModel: OTHER
CameraDetector: GATAN K2 SUMMIT (4k x 4k)

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Image processing

ProcessingMethod: single particle reconstruction / Number of projections: 145000
3D reconstructionResolution: 2.88 Å / Resolution method: FSC 0.143 CUT-OFF

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Atomic model buiding

Output model

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