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- EMDB-23278: Cryo-EM structure of ligand-free Human SARM1 -

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Basic information

Entry
Database: EMDB / ID: EMD-23278
TitleCryo-EM structure of ligand-free Human SARM1
Map dataDeepEMhancer post-processed map
Sample
  • Complex: homo-octameric SARM1
    • Protein or peptide: NAD(+) hydrolase SARM1
KeywordsNADase / Autoinhibition / Neurodegeneration / Allostery / NAD / Toxin / Hydrolase / SIGNALING PROTEIN
Function / homology
Function and homology information


negative regulation of MyD88-independent toll-like receptor signaling pathway / MyD88-independent TLR4 cascade / Toll Like Receptor 3 (TLR3) Cascade / NADP+ nucleosidase activity / NAD catabolic process / ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase / NAD+ nucleosidase activity / protein localization to mitochondrion / NAD+ nucleotidase, cyclic ADP-ribose generating / nervous system process ...negative regulation of MyD88-independent toll-like receptor signaling pathway / MyD88-independent TLR4 cascade / Toll Like Receptor 3 (TLR3) Cascade / NADP+ nucleosidase activity / NAD catabolic process / ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase / NAD+ nucleosidase activity / protein localization to mitochondrion / NAD+ nucleotidase, cyclic ADP-ribose generating / nervous system process / Hydrolases; Glycosylases; Hydrolysing N-glycosyl compounds / regulation of dendrite morphogenesis / response to axon injury / response to glucose / 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 / nervous system development / mitochondrial outer membrane / microtubule / cell differentiation / axon / innate immune response / dendrite / synapse / cell surface / signal transduction / protein-containing complex / 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
NAD(+) hydrolase SARM1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsNanson JD / Gu W
Funding support Australia, 6 items
OrganizationGrant numberCountry
National Health and Medical Research Council (NHMRC, Australia)1107804 Australia
National Health and Medical Research Council (NHMRC, Australia)1160570 Australia
National Health and Medical Research Council (NHMRC, Australia)1071659 Australia
National Health and Medical Research Council (NHMRC, Australia)1108859 Australia
Australian Research Council (ARC)FL180100109 Australia
Australian Research Council (ARC)DE170100783 Australia
CitationJournal: Neuron / Year: 2021
Title: SARM1 is a metabolic sensor activated by an increased NMN/NAD ratio to trigger axon degeneration.
Authors: Matthew D Figley / Weixi Gu / Jeffrey D Nanson / Yun Shi / Yo Sasaki / Katie Cunnea / Alpeshkumar K Malde / Xinying Jia / Zhenyao Luo / Forhad K Saikot / Tamim Mosaiab / Veronika Masic / ...Authors: Matthew D Figley / Weixi Gu / Jeffrey D Nanson / Yun Shi / Yo Sasaki / Katie Cunnea / Alpeshkumar K Malde / Xinying Jia / Zhenyao Luo / Forhad K Saikot / Tamim Mosaiab / Veronika Masic / Stephanie Holt / Lauren Hartley-Tassell / Helen Y McGuinness / Mohammad K Manik / Todd Bosanac / Michael J Landsberg / Philip S Kerry / Mehdi Mobli / Robert O Hughes / Jeffrey Milbrandt / Bostjan Kobe / Aaron DiAntonio / Thomas Ve /
Abstract: Axon degeneration is a central pathological feature of many neurodegenerative diseases. Sterile alpha and Toll/interleukin-1 receptor motif-containing 1 (SARM1) is a nicotinamide adenine dinucleotide ...Axon degeneration is a central pathological feature of many neurodegenerative diseases. Sterile alpha and Toll/interleukin-1 receptor motif-containing 1 (SARM1) is a nicotinamide adenine dinucleotide (NAD)-cleaving enzyme whose activation triggers axon destruction. Loss of the biosynthetic enzyme NMNAT2, which converts nicotinamide mononucleotide (NMN) to NAD, activates SARM1 via an unknown mechanism. Using structural, biochemical, biophysical, and cellular assays, we demonstrate that SARM1 is activated by an increase in the ratio of NMN to NAD and show that both metabolites compete for binding to the auto-inhibitory N-terminal armadillo repeat (ARM) domain of SARM1. We report structures of the SARM1 ARM domain bound to NMN and of the homo-octameric SARM1 complex in the absence of ligands. We show that NMN influences the structure of SARM1 and demonstrate via mutagenesis that NMN binding is required for injury-induced SARM1 activation and axon destruction. Hence, SARM1 is a metabolic sensor responding to an increased NMN/NAD ratio by cleaving residual NAD, thereby inducing feedforward metabolic catastrophe and axonal demise.
History
DepositionJan 12, 2021-
Header (metadata) releaseMar 10, 2021-
Map releaseMar 10, 2021-
UpdateMar 6, 2024-
Current statusMar 6, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.07
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.07
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7ld0
  • Surface level: 0.07
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_23278.png

Downloads & links

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Map

FileDownload / File: emd_23278.map.gz / Format: CCP4 / Size: 166.4 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationDeepEMhancer post-processed map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.09 Å/pix.
x 352 pix.
= 383.68 Å		1.09 Å/pix.
x 352 pix.
= 383.68 Å		1.09 Å/pix.
x 352 pix.
= 383.68 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.09 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.07 / Movie #1: 0.07
Minimum - Maximum-0.030226938 - 1.8801286
Average (Standard dev.)0.0015251942 (±0.025672989)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions352352352
Spacing352352352
CellA=B=C: 383.68002 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.091.091.09
M x/y/z352352352
origin x/y/z0.0000.0000.000
length x/y/z383.680383.680383.680
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ296296296
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS352352352
D min/max/mean-0.0301.8800.002

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Supplemental data

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Mask #1

Fileemd_23278_msk_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: Refined map

Fileemd_23278_additional_1.map
AnnotationRefined map
Projections & Slices
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Histogram

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Half map: Half map A

Fileemd_23278_half_map_1.map
AnnotationHalf map A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map B

Fileemd_23278_half_map_2.map
AnnotationHalf map B
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Sample components

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Entire : homo-octameric SARM1

EntireName: homo-octameric SARM1
Components
  • Complex: homo-octameric SARM1
    • Protein or peptide: NAD(+) hydrolase SARM1

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Supramolecule #1: homo-octameric SARM1

SupramoleculeName: homo-octameric SARM1 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: NAD(+) hydrolase SARM1

MacromoleculeName: NAD(+) hydrolase SARM1 / 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: 76.471469 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: LAVPGPDGGG GTGPWWAAGG RGPREVSPGA GTEVQDALER ALPELQQALS ALKQAGGARA VGAGLAEVFQ LVEEAWLLPA VGREVAQGL CDAIRLDGGL DLLLRLLQAP ELETRVQAAR LLEQILVAEN RDRVARIGLG VILNLAKERE PVELARSVAG I LEHMFKHS ...String:
LAVPGPDGGG GTGPWWAAGG RGPREVSPGA GTEVQDALER ALPELQQALS ALKQAGGARA VGAGLAEVFQ LVEEAWLLPA VGREVAQGL CDAIRLDGGL DLLLRLLQAP ELETRVQAAR LLEQILVAEN RDRVARIGLG VILNLAKERE PVELARSVAG I LEHMFKHS EETCQRLVAA GGLDAVLYWC RRTDPALLRH CALALGNCAL HGGQAVQRRM VEKRAAEWLF PLAFSKEDEL LR LHACLAV AVLATNKEVE REVERSGTLA LVEPLVASLD PGRFARCLVD ASDTSQGRGP DDLQRLVPLL DSNRLEAQCI GAF YLCAEA AIKSLQGKTK VFSDIGAIQS LKRLVSYSTN GTKSALAKRA LRLLGEEVPR PILPSVPSWK EAEVQTWLQQ IGFS KYCES FREQQVDGDL LLRLTEEELQ TDLGMKSGIT RKRFFRELTE LKTFANYSTC DRSNLADWLG SLDPRFRQYT YGLVS CGLD RSLLHRVSEQ QLLEDCGIHL GVHRARILTA AREMLHSPLP CTGGKPSGDT PDVFISYRRN SGSQLASLLK VHLQLH GFS VFIDVEKLEA GKFEDKLIQS VMGARNFVLV LSPGALDKCM QDHDCKDWVH KEIVTALSCG KNIVPIIDGF EWPEPQV LP EDMQAVLTFN GIKWSHEYQE ATIEKIIRFL QGRSSRDSSA GSDTSLEGAA PMGPT

UniProtKB: NAD(+) hydrolase SARM1

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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

Concentration0.27 mg/mL
BufferpH: 7.4
Component:
ConcentrationName
25.0 mMHEPES
150.0 mMSodium Chloride
0.4 %Glycerol
0.1 mMTCEP
GridModel: Quantifoil R2/2 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: CONTINUOUS / Support film - Film thickness: 6 / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Specialist opticsEnergy filter - Slit width: 20 eV
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average exposure time: 4.99 sec. / Average electron dose: 54.0 e/Å2
Details: exposure rate of 12.88e-/pixel/second super-resolution 0.543 A/pixel 45 frames per image
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionApplied symmetry - Point group: C8 (8 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 275460
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final 3D classificationSoftware - Name: cryoSPARC
FSC plot (resolution estimation)

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