+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-11190 | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
Title | SARM1 SAM1-2 domains | |||||||||
Map data | ||||||||||
Sample |
| |||||||||
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 / regulation of neuron apoptotic process / response to glucose / 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 | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 7.7 Å | |||||||||
Authors | Sporny 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
| |||||||||
Citation | Journal: 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 |
|
-Structure visualization
Movie |
Movie viewer |
---|---|
Structure viewer | EM map: SurfViewMolmilJmol/JSmol |
Supplemental images |
-Downloads & links
-EMDB archive
Map data | emd_11190.map.gz | 59.4 MB | EMDB map data format | |
---|---|---|---|---|
Header (meta data) | emd-11190-v30.xml emd-11190.xml | 11.4 KB 11.4 KB | Display Display | EMDB header |
Images | emd_11190.png | 132 KB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-11190 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-11190 | HTTPS FTP |
-Validation report
Summary document | emd_11190_validation.pdf.gz | 225.7 KB | Display | EMDB validaton report |
---|---|---|---|---|
Full document | emd_11190_full_validation.pdf.gz | 224.8 KB | Display | |
Data in XML | emd_11190_validation.xml.gz | 6.1 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-11190 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-11190 | HTTPS FTP |
-Related structure data
Related structure data | 6zg0MC 6zfxC 6zg1C 7anwC M: atomic model generated by this map C: citing same article (ref.) |
---|---|
Similar structure data |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
---|---|
Related items in Molecule of the Month |
-Map
File | Download / File: emd_11190.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.1 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
|
-Supplemental data
-Sample components
-Entire : hSARM1
Entire | Name: hSARM1 |
---|---|
Components |
|
-Supramolecule #1: hSARM1
Supramolecule | Name: hSARM1 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 |
---|---|
Source (natural) | Organism: Homo sapiens (human) |
Recombinant expression | Organism: Homo sapiens (human) |
-Macromolecule #1: NAD(+) hydrolase SARM1
Macromolecule | Name: 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 weight | Theoretical: 79.971258 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: 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 |
-Macromolecule #2: 1,2-ETHANEDIOL
Macromolecule | Name: 1,2-ETHANEDIOL / type: ligand / ID: 2 / Number of copies: 17 / Formula: EDO |
---|---|
Molecular weight | Theoretical: 62.068 Da |
Chemical component information | ChemComp-EDO: |
-Macromolecule #3: BETA-MERCAPTOETHANOL
Macromolecule | Name: BETA-MERCAPTOETHANOL / type: ligand / ID: 3 / Number of copies: 8 / Formula: BME |
---|---|
Molecular weight | Theoretical: 78.133 Da |
Chemical component information | ChemComp-BME: |
-Macromolecule #4: DI(HYDROXYETHYL)ETHER
Macromolecule | Name: DI(HYDROXYETHYL)ETHER / type: ligand / ID: 4 / Number of copies: 2 / Formula: PEG |
---|---|
Molecular weight | Theoretical: 106.12 Da |
Chemical component information | ChemComp-PEG: |
-Macromolecule #5: TRIETHYLENE GLYCOL
Macromolecule | Name: TRIETHYLENE GLYCOL / type: ligand / ID: 5 / Number of copies: 1 / Formula: PGE |
---|---|
Molecular weight | Theoretical: 150.173 Da |
Chemical component information | ChemComp-PGE: |
-Experimental details
-Structure determination
Method | cryo EM |
---|---|
Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 8.8 |
---|---|
Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI POLARA 300 |
---|---|
Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 80.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD |
Experimental equipment | Model: Tecnai Polara / Image courtesy: FEI Company |
-Image processing
Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 7.7 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 5410 |
---|---|
Initial angle assignment | Type: ANGULAR RECONSTITUTION |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |