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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
Sample
  • Complex: hSARM1
    • Protein or peptide: NAD(+) hydrolase SARM1
  • Ligand: (~{E})-4-methylnon-4-enedial
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 / NAD catabolic process / NAD+ nucleosidase activity / ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase / protein localization to mitochondrion / NAD+ nucleotidase, cyclic ADP-ribose generating / NADP+ nucleosidase activity / nervous system process ...negative regulation of MyD88-independent toll-like receptor signaling pathway / MyD88-independent TLR4 cascade / Toll Like Receptor 3 (TLR3) Cascade / NAD catabolic process / NAD+ nucleosidase activity / ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase / protein localization to mitochondrion / NAD+ nucleotidase, cyclic ADP-ribose generating / NADP+ nucleosidase activity / nervous system process / Hydrolases; Glycosylases; Hydrolysing N-glycosyl compounds / regulation of dendrite morphogenesis / response to axon injury / response to glucose / signaling adaptor activity / regulation of neuron apoptotic process / 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 / microtubule / mitochondrial outer membrane / cell differentiation / axon / innate immune response / dendrite / synapse / 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
NAD(+) hydrolase SARM1
Similarity search - Component
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.
History
DepositionJun 18, 2020-
Header (metadata) releaseNov 18, 2020-
Map releaseNov 18, 2020-
UpdateNov 9, 2022-
Current statusNov 9, 2022Processing 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

emd_11187.png

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)
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
start NX/NY/NZ000
NX/NY/NZ240240240
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
Components
  • Complex: hSARM1
    • Protein or peptide: NAD(+) hydrolase SARM1
  • Ligand: (~{E})-4-methylnon-4-enedial

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Supramolecule #1: hSARM1

SupramoleculeName: hSARM1 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human) / Recombinant cell: HEK293F

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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: 79.971258 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MSYHHHHHHD YDIPTTENLY FQGAMGSERL AVPGPDGGGG TGPWWAAGGR GPREVSPGAG TEVQDALERA LPELQQALSA LKQAGGARA VGAGLAEVFQ LVEEAWLLPA VGREVAQGLC DAIRLDGGLD LLLRLLQAPE LETRVQAARL LEQILVAENR D RVARIGLG ...String:
MSYHHHHHHD YDIPTTENLY FQGAMGSERL AVPGPDGGGG TGPWWAAGGR GPREVSPGAG TEVQDALERA LPELQQALSA LKQAGGARA VGAGLAEVFQ LVEEAWLLPA VGREVAQGLC DAIRLDGGLD LLLRLLQAPE LETRVQAARL LEQILVAENR D RVARIGLG VILNLAKERE PVELARSVAG ILEHMFKHSE ETCQRLVAAG GLDAVLYWCR RTDPALLRHC ALALGNCALH GG QAVQRRM VEKRAAEWLF PLAFSKEDEL LRLHACLAVA VLATNKEVER EVERSGTLAL VEPLVASLDP GRFARCLVDA SDT SQGRGP DDLQRLVPLL DSNRLEAQCI GAFYLCAEAA IKSLQGKTKV FSDIGAIQSL KRLVSYSTNG TKSALAKRAL RLLG EEVPR PILPSVPSWK EAEVQTWLQQ IGFSKYCESF REQQVDGDLL LRLTEEELQT DLGMKSGITR KRFFRELTEL KTFAN YSTC DRSNLADWLG SLDPRFRQYT YGLVSCGLDR SLLHRVSEQQ LLEDCGIHLG VHRARILTAA REMLHSPLPC TGGKPS GDT PDVFISYRRN SGSQLASLLK VHLQLHGFSV FIDVEKLEAG KFEDKLIQSV MGARNFVLVL SPGALDKCMQ DHDCKDW VH KQIVTALSCG KNIVPIIDGF EWPEPQVLPE DMQAVLTFNG IKWSHEYQEA TIEKIIRFLQ GRSSRDSSAG SDTSLEGA A PMGPT

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Macromolecule #2: (~{E})-4-methylnon-4-enedial

MacromoleculeName: (~{E})-4-methylnon-4-enedial / type: ligand / ID: 2 / Number of copies: 16 / Formula: S1N
Molecular weightTheoretical: 168.233 Da
Chemical component information

ChemComp-S1N:
(~{E})-4-methylnon-4-enedial

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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: 8.8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recording#0 - Image recording ID: 1 / #0 - Film or detector model: GATAN K2 SUMMIT (4k x 4k) / #0 - Average electron dose: 50.0 e/Å2 / #1 - Image recording ID: 2 / #1 - Film or detector model: GATAN K2 SUMMIT (4k x 4k) / #1 - Average electron dose: 50.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.88 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 145000
Image recording ID1

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