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- EMDB-30402: NAD+-bound Sarm1 in the self-inhibited state -

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Basic information

Entry
Database: EMDB / ID: EMD-30402
TitleNAD+-bound Sarm1 in the self-inhibited state
Map data
Sample
  • Complex: Octamer of full-length Sarm1
    • Protein or peptide: NAD(+) hydrolase SARM1
  • Ligand: NICOTINAMIDE-ADENINE-DINUCLEOTIDE
KeywordsNADase / ARM / SAM / TIR / HYDROLASE
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: 3.0 Å
AuthorsZhang Z / Jiang Y
CitationJournal: 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.
History
DepositionJul 25, 2020-
Header (metadata) releaseOct 21, 2020-
Map releaseOct 21, 2020-
UpdateMar 27, 2024-
Current statusMar 27, 2024Processing site: PDBj / Status: Released

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Structure visualization

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  • Surface view colored by cylindrical radius
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  • Surface view with fitted model
  • Atomic models: PDB-7cm6
  • Surface level: 0.02
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-7cm6
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Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_30402.png

Downloads & links

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Map

FileDownload / File: emd_30402.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.06 Å/pix.
x 384 pix.
= 405.12 Å		1.06 Å/pix.
x 384 pix.
= 405.12 Å		1.06 Å/pix.
x 384 pix.
= 405.12 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.055 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.02 / Movie #1: 0.02
Minimum - Maximum-0.06811115 - 0.13721603
Average (Standard dev.)0.000026925341 (±0.0038909034)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 405.12 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0551.0551.055
M x/y/z384384384
origin x/y/z0.0000.0000.000
length x/y/z405.120405.120405.120
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ304304304
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS384384384
D min/max/mean-0.0680.1370.000

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Supplemental data

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Sample components

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Entire : Octamer of full-length Sarm1

EntireName: Octamer of full-length Sarm1
Components
  • Complex: Octamer of full-length Sarm1
    • Protein or peptide: NAD(+) hydrolase SARM1
  • Ligand: NICOTINAMIDE-ADENINE-DINUCLEOTIDE

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Supramolecule #1: Octamer of full-length Sarm1

SupramoleculeName: Octamer of full-length Sarm1 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 640 kDa/nm

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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: 80.504289 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MVLTLLLSAY KLCRFFAMSG PRPGAERLAV PGPDGGGGTG PWWAAGGRGP REVSPGAGTE VQDALERALP ELQQALSALK QAGGARAVG AGLAEVFQLV EEAWLLPAVG REVAQGLCDA IRLDGGLDLL LRLLQAPELE TRVQAARLLE QILVAENRDR V ARIGLGVI ...String:
MVLTLLLSAY KLCRFFAMSG PRPGAERLAV PGPDGGGGTG PWWAAGGRGP REVSPGAGTE VQDALERALP ELQQALSALK QAGGARAVG AGLAEVFQLV EEAWLLPAVG REVAQGLCDA IRLDGGLDLL LRLLQAPELE TRVQAARLLE QILVAENRDR V ARIGLGVI LNLAKEREPV ELARSVAGIL EHMFKHSEET CQRLVAAGGL DAVLYWCRRT DPALLRHCAL ALGNCALHGG QA VQRRMVE KRAAEWLFPL AFSKEDELLR LHACLAVAVL ATNKEVEREV ERSGTLALVE PLVASLDPGR FARCLVDASD TSQ GRGPDD LQRLVPLLDS NRLEAQCIGA FYLCAEAAIK SLQGKTKVFS DIGAIQSLKR LVSYSTNGTK SALAKRALRL LGEE VPRPI LPSVPSWKEA EVQTWLQQIG FSKYCESFRE QQVDGDLLLR LTEEELQTDL GMKSGITRKR FFRELTELKT FANYS TCDR SNLADWLGSL DPRFRQYTYG LVSCGLDRSL LHRVSEQQLL EDCGIHLGVH RARILTAARE MLHSPLPCTG GKPSGD TPD VFISYRRNSG SQLASLLKVH LQLHGFSVFI DVEKLEAGKF EDKLIQSVMG ARNFVLVLSP GALDKCMQDH DCKDWVH KE IVTALSCGKN IVPIIDGFEW PEPQVLPEDM QAVLTFNGIK WSHEYQEATI EKIIRFLQGR SSRDSSAGSD TSLEGAAP M GPTSNSLEVL FQ

UniProtKB: NAD(+) hydrolase SARM1

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Macromolecule #2: NICOTINAMIDE-ADENINE-DINUCLEOTIDE

MacromoleculeName: NICOTINAMIDE-ADENINE-DINUCLEOTIDE / type: ligand / ID: 2 / Number of copies: 8 / Formula: NAD
Molecular weightTheoretical: 663.425 Da
Chemical component information

ChemComp-NAD:
NICOTINAMIDE-ADENINE-DINUCLEOTIDE / NAD*YM

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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

Concentration3 mg/mL
BufferpH: 8
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 400 / Pretreatment - Type: PLASMA CLEANING / Pretreatment - Time: 30 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 283 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 57.5 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 466398
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 57708
Initial angle assignmentType: ANGULAR RECONSTITUTION / Software - Name: RELION
Final angle assignmentType: ANGULAR RECONSTITUTION / Software - Name: RELION
Final 3D classificationNumber classes: 6 / Software - Name: RELION

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