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- EMDB-17369: A CHIMERA construct containing human SARM1 ARM and SAM domains an... -

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Basic information

Entry
Database: EMDB / ID: EMD-17369
TitleA CHIMERA construct containing human SARM1 ARM and SAM domains and C. elegans TIR domain.
Map data
Sample
  • Complex: A CHIMERA construct containing human SARM1 ARM and SAM domains and C. elegans TIR domain.
    • Protein or peptide: NAD(+) hydrolase SARM1,NAD(+) hydrolase tir-1
  • Ligand: NICOTINAMIDE-ADENINE-DINUCLEOTIDE
KeywordsSARM1 / TIR-1 / C. elegans / neurodegeneration / cryo-EM / structural biology / NAD+ metabolism / axon Wallerian degeneration / HYDROLASE
Function / homology
Function and homology information


serotonin biosynthetic 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 ...serotonin biosynthetic 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 / cell fate specification / Hydrolases; Glycosylases; Hydrolysing N-glycosyl compounds / regulation of dendrite morphogenesis / response to axon injury / defense response to fungus / response to glucose / regulation of neuron apoptotic process / signaling adaptor activity / axon cytoplasm / TRAF6-mediated induction of TAK1 complex within TLR4 complex / Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE) / IKK complex recruitment mediated by RIP1 / small GTPase binding / protein localization / cell-cell signaling / nervous system development / cell body / defense response to Gram-negative bacterium / mitochondrial outer membrane / microtubule / cell differentiation / defense response to bacterium / axon / negative regulation of gene expression / innate immune response / dendrite / synapse / positive regulation of gene expression / protein kinase binding / cell surface / signal transduction / positive regulation of transcription by RNA polymerase II / protein-containing complex / mitochondrion / identical protein binding / cytosol / cytoplasm
Similarity search - Function
Sterile alpha and TIR motif-containing protein 1 / TIR domain / SAM domain (Sterile alpha motif) / 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 and TIR motif-containing protein 1 / TIR domain / SAM domain (Sterile alpha motif) / 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 / NAD(+) hydrolase tir-1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.68 Å
AuthorsIsupov MN / Opatowsky Y
Funding support Israel, United States, 3 items
OrganizationGrant numberCountry
Israel Science Foundation1425/15 Israel
Israel Science Foundation909/19 Israel
United States - Israel Binational Science Foundation (BSF)2019150 United States
CitationJournal: Cell Rep / Year: 2023
Title: Structure-function analysis of ceTIR-1/hSARM1 explains the lack of Wallerian axonal degeneration in C. elegans.
Authors: Tami Khazma / Atira Grossman / Julia Guez-Haddad / Chengye Feng / Hadas Dabas / Radhika Sain / Michal Weitman / Ran Zalk / Michail N Isupov / Marc Hammarlund / Michael Hons / Yarden Opatowsky /
Abstract: Wallerian axonal degeneration (WD) does not occur in the nematode C. elegans, in contrast to other model animals. However, WD depends on the NADase activity of SARM1, a protein that is also expressed ...Wallerian axonal degeneration (WD) does not occur in the nematode C. elegans, in contrast to other model animals. However, WD depends on the NADase activity of SARM1, a protein that is also expressed in C. elegans (ceSARM/ceTIR-1). We hypothesized that differences in SARM between species might exist and account for the divergence in WD. We first show that expression of the human (h)SARM1, but not ceTIR-1, in C. elegans neurons is sufficient to confer axon degeneration after nerve injury. Next, we determined the cryoelectron microscopy structure of ceTIR-1 and found that, unlike hSARM1, which exists as an auto-inhibited ring octamer, ceTIR-1 forms a readily active 9-mer. Enzymatically, the NADase activity of ceTIR-1 is substantially weaker (10-fold higher Km) than that of hSARM1, and even when fully active, it falls short of consuming all cellular NAD. Our experiments provide insight into the molecular mechanisms and evolution of SARM orthologs and WD across species.
History
DepositionMay 16, 2023-
Header (metadata) releaseSep 6, 2023-
Map releaseSep 6, 2023-
UpdateSep 6, 2023-
Current statusSep 6, 2023Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_17369.png

Downloads & links

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Map

FileDownload / File: emd_17369.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.84 Å/pix.
x 300 pix.
= 252. Å		0.84 Å/pix.
x 300 pix.
= 252. Å		0.84 Å/pix.
x 300 pix.
= 252. Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.84 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.16
Minimum - Maximum-0.419608 - 0.90842026
Average (Standard dev.)0.003909335 (±0.038600586)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 251.99998 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_17369_half_map_1.map
Projections & Slices
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Slices (1/2)
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Histogram

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Half map: #1

Fileemd_17369_half_map_2.map
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Sample components

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Entire : A CHIMERA construct containing human SARM1 ARM and SAM domains an...

EntireName: A CHIMERA construct containing human SARM1 ARM and SAM domains and C. elegans TIR domain.
Components
  • Complex: A CHIMERA construct containing human SARM1 ARM and SAM domains and C. elegans TIR domain.
    • Protein or peptide: NAD(+) hydrolase SARM1,NAD(+) hydrolase tir-1
  • Ligand: NICOTINAMIDE-ADENINE-DINUCLEOTIDE

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Supramolecule #1: A CHIMERA construct containing human SARM1 ARM and SAM domains an...

SupramoleculeName: A CHIMERA construct containing human SARM1 ARM and SAM domains and C. elegans TIR domain.
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: NAD(+) hydrolase SARM1,NAD(+) hydrolase tir-1

MacromoleculeName: NAD(+) hydrolase SARM1,NAD(+) hydrolase tir-1 / type: protein_or_peptide / ID: 1 / Number of copies: 16 / Enantiomer: LEVO / EC number: ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 81.070656 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 PDVFISYRRS TGNQLASLIK VLLQLRGYRV FIDVDKLYAG KFDSSLLKNI QAAKHFILVL TPNSLDRLLN DDNCEDW VH KELKCAFEHQ KNIIPIFDTA FEFPTKEDQI PNDIRMITKY NGVKWVHDYQ DACMAKVVRF ITGELNRTTP TTKEMPSI S RKTTQQR

UniProtKB: NAD(+) hydrolase SARM1, NAD(+) hydrolase tir-1

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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

BufferpH: 8.5
GridModel: Quantifoil R1.2/1.3 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 60 sec.
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Specialist opticsEnergy filter - Name: GIF Quantum LS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 41.4 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.8000000000000003 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 298564
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.68 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 136346
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final angle assignmentType: COMMON LINE / Software - Name: cryoSPARC
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial model
PDB IDChainDetails

7anw

residue_range: 26-560, source_name: Other, initial_model_type: experimental modelThe initial octameric model containing human ARM and SAM domains
residue_range: 561-708, source_name: AlphaFold, initial_model_type: in silico model
RefinementSpace: RECIPROCAL / Protocol: FLEXIBLE FIT
Output model

PDB-8p2l:
A CHIMERA construct containing human SARM1 ARM and SAM domains and C. elegans TIR domain.

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