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- EMDB-21869: SARM1 with ARM Domain Deleted -

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Basic information

Entry
Database: EMDB / ID: EMD-21869
TitleSARM1 with ARM Domain Deleted
Map dataSARM1 with ARM Domain Deleted
Sample
  • Complex: SARM1 with ARM domains deleted
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 6.8 Å
AuthorsXie T / Bratkowski M / Sambashivan S / Bai X
Funding support United States, 3 items
OrganizationGrant numberCountry
Cancer Prevention and Research Institute of Texas (CPRIT)RR160082 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01136976 United States
Welch FoundationI-1944-20180324 United States
CitationJournal: Cell Rep / Year: 2020
Title: Structural and Mechanistic Regulation of the Pro-degenerative NAD Hydrolase SARM1.
Authors: Matthew Bratkowski / Tian Xie / Desiree A Thayer / Shradha Lad / Prakhyat Mathur / Yu-San Yang / Gregory Danko / Thomas C Burdett / Jean Danao / Aaron Cantor / Jennifer A Kozak / Sean P ...Authors: Matthew Bratkowski / Tian Xie / Desiree A Thayer / Shradha Lad / Prakhyat Mathur / Yu-San Yang / Gregory Danko / Thomas C Burdett / Jean Danao / Aaron Cantor / Jennifer A Kozak / Sean P Brown / Xiaochen Bai / Shilpa Sambashivan /
Abstract: The NADase SARM1 is a central switch in injury-activated axon degeneration, an early hallmark of many neurological diseases. Here, we present cryo-electron microscopy (cryo-EM) structures of ...The NADase SARM1 is a central switch in injury-activated axon degeneration, an early hallmark of many neurological diseases. Here, we present cryo-electron microscopy (cryo-EM) structures of autoinhibited (3.3 Å) and active SARM1 (6.8 Å) and provide mechanistic insight into the tight regulation of SARM1's function by the local metabolic environment. Although both states retain an octameric core, the defining feature of the autoinhibited state is a lock between the autoinhibitory Armadillo/HEAT motif (ARM) and catalytic Toll/interleukin-1 receptor (TIR) domains, which traps SARM1 in an inactive state. Mutations that break this lock activate SARM1, resulting in catastrophic neuronal death. Notably, the mutants cannot be further activated by the endogenous activator nicotinamide mononucleotide (NMN), and active SARM1 is product inhibited by Nicotinamide (NAM), highlighting SARM1's functional dependence on key metabolites in the NAD salvage pathway. Our studies provide a molecular understanding of SARM1's transition from an autoinhibited to an injury-activated state and lay the foundation for future SARM1-based therapies to treat axonopathies.
History
DepositionApr 28, 2020-
Header (metadata) releaseAug 12, 2020-
Map releaseAug 12, 2020-
UpdateAug 12, 2020-
Current statusAug 12, 2020Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.015
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by cylindrical radius
  • Surface level: 0.015
  • Imaged by UCSF Chimera
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Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_21869.png

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Map

FileDownload / File: emd_21869.map.gz / Format: CCP4 / Size: 22.2 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationSARM1 with ARM Domain Deleted
Voxel sizeX=Y=Z: 1.07 Å
Density
Contour LevelBy AUTHOR: 0.0185 / Movie #1: 0.015
Minimum - Maximum-0.017147942 - 0.054630592
Average (Standard dev.)0.0006877768 (±0.0036823105)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions180180180
Spacing180180180
CellA=B=C: 192.6 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.071.071.07
M x/y/z180180180
origin x/y/z0.0000.0000.000
length x/y/z192.600192.600192.600
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ250250250
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS180180180
D min/max/mean-0.0170.0550.001

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Supplemental data

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Sample components

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Entire : SARM1 with ARM domains deleted

EntireName: SARM1 with ARM domains deleted
Components
  • Complex: SARM1 with ARM domains deleted

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Supramolecule #1: SARM1 with ARM domains deleted

SupramoleculeName: SARM1 with ARM domains deleted / type: complex / ID: 1 / Parent: 0 / Details: Octamer
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Escherichia coli (E. coli)

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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: 7.4
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Specialist opticsEnergy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Calibrated magnification: 46729 / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 496131
CTF correctionSoftware: (Name: RELION, Gctf)
Startup modelType of model: OTHER / Details: Initial model was generated in RELION
Final reconstructionNumber classes used: 6 / Applied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 6.8 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION
Details: This map was one of the 6 classes from 3D classification of RELION.
Number images used: 27415
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION
Final angle assignmentType: PROJECTION MATCHING / Software - Name: RELION

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