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- PDB-5wkb: MicroED structure of the segment, NFGEFS, from the A315E familial... -

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Basic information

Entry
Database: PDB / ID: 5wkb
TitleMicroED structure of the segment, NFGEFS, from the A315E familial variant of the low complexity domain of TDP-43, residues 312-317
ComponentsTAR DNA-binding protein 43
KeywordsPROTEIN FIBRIL / Amyloid / LARKS / TDP-43
Function / homology
Function and homology information


nuclear inner membrane organization / interchromatin granule / perichromatin fibrils / 3'-UTR-mediated mRNA destabilization / 3'-UTR-mediated mRNA stabilization / intracellular membraneless organelle / negative regulation of protein phosphorylation / host-mediated suppression of viral transcription / pre-mRNA intronic binding / RNA splicing ...nuclear inner membrane organization / interchromatin granule / perichromatin fibrils / 3'-UTR-mediated mRNA destabilization / 3'-UTR-mediated mRNA stabilization / intracellular membraneless organelle / negative regulation of protein phosphorylation / host-mediated suppression of viral transcription / pre-mRNA intronic binding / RNA splicing / response to endoplasmic reticulum stress / mRNA 3'-UTR binding / molecular condensate scaffold activity / positive regulation of insulin secretion / regulation of circadian rhythm / regulation of protein stability / positive regulation of protein import into nucleus / mRNA processing / cytoplasmic stress granule / rhythmic process / regulation of gene expression / double-stranded DNA binding / regulation of apoptotic process / amyloid fibril formation / regulation of cell cycle / nuclear speck / RNA polymerase II cis-regulatory region sequence-specific DNA binding / negative regulation of gene expression / lipid binding / chromatin / mitochondrion / DNA binding / RNA binding / nucleoplasm / identical protein binding / nucleus
Similarity search - Function
TAR DNA-binding protein 43, N-terminal / : / TAR DNA-binding protein 43, N-terminal domain / TAR DNA-binding protein 43, C-terminal / RNA recognition motif / RNA recognition motif / Eukaryotic RNA Recognition Motif (RRM) profile. / RNA recognition motif domain / RNA-binding domain superfamily / Nucleotide-binding alpha-beta plait domain superfamily
Similarity search - Domain/homology
TAR DNA-binding protein 43
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON CRYSTALLOGRAPHY / electron crystallography / AB INITIO PHASING / cryo EM / Resolution: 1 Å
AuthorsGuenther, E.L. / Sawaya, M.R. / Cascio, D. / Eisenberg, D.S.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute on Aging (NIH/NIA)NIH NIA AG029430 United States
CitationJournal: Nat Struct Mol Biol / Year: 2018
Title: Atomic structures of TDP-43 LCD segments and insights into reversible or pathogenic aggregation.
Authors: Elizabeth L Guenther / Qin Cao / Hamilton Trinh / Jiahui Lu / Michael R Sawaya / Duilio Cascio / David R Boyer / Jose A Rodriguez / Michael P Hughes / David S Eisenberg /
Abstract: The normally soluble TAR DNA-binding protein 43 (TDP-43) is found aggregated both in reversible stress granules and in irreversible pathogenic amyloid. In TDP-43, the low-complexity domain (LCD) is ...The normally soluble TAR DNA-binding protein 43 (TDP-43) is found aggregated both in reversible stress granules and in irreversible pathogenic amyloid. In TDP-43, the low-complexity domain (LCD) is believed to be involved in both types of aggregation. To uncover the structural origins of these two modes of β-sheet-rich aggregation, we have determined ten structures of segments of the LCD of human TDP-43. Six of these segments form steric zippers characteristic of the spines of pathogenic amyloid fibrils; four others form LARKS, the labile amyloid-like interactions characteristic of protein hydrogels and proteins found in membraneless organelles, including stress granules. Supporting a hypothetical pathway from reversible to irreversible amyloid aggregation, we found that familial ALS variants of TDP-43 convert LARKS to irreversible aggregates. Our structures suggest how TDP-43 adopts both reversible and irreversible β-sheet aggregates and the role of mutation in the possible transition of reversible to irreversible pathogenic aggregation.
History
DepositionJul 24, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 23, 2018Provider: repository / Type: Initial release
Revision 1.1May 30, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.title
Revision 1.2Jun 6, 2018Group: Data collection / Database references / Category: citation / diffrn_source
Item: _citation.journal_abbrev / _citation.pdbx_database_id_PubMed ..._citation.journal_abbrev / _citation.pdbx_database_id_PubMed / _citation.title / _diffrn_source.source
Revision 1.3Jun 20, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.4Dec 18, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.5Jun 30, 2021Group: Data collection / Category: diffrn_detector / Item: _diffrn_detector.detector
Revision 1.6Mar 13, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

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Assembly

Deposited unit
A: TAR DNA-binding protein 43


Theoretical massNumber of molelcules
Total (without water)7001
Polymers7001
Non-polymers00
Water362
1
A: TAR DNA-binding protein 43

A: TAR DNA-binding protein 43

A: TAR DNA-binding protein 43

A: TAR DNA-binding protein 43

A: TAR DNA-binding protein 43

A: TAR DNA-binding protein 43

A: TAR DNA-binding protein 43

A: TAR DNA-binding protein 43

A: TAR DNA-binding protein 43

A: TAR DNA-binding protein 43


Theoretical massNumber of molelcules
Total (without water)6,99710
Polymers6,99710
Non-polymers00
Water18010
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation1_556x,y,z+11
crystal symmetry operation1_557x,y,z+21
crystal symmetry operation1_554x,y,z-11
crystal symmetry operation1_553x,y,z-21
crystal symmetry operation3_645-x+3/2,y-1/2,-z1
crystal symmetry operation3_646-x+3/2,y-1/2,-z+11
crystal symmetry operation3_647-x+3/2,y-1/2,-z+21
crystal symmetry operation3_644-x+3/2,y-1/2,-z-11
crystal symmetry operation3_643-x+3/2,y-1/2,-z-21
Unit cell
Length a, b, c (Å)42.770, 17.420, 4.900
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212

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Components

#1: Protein/peptide TAR DNA-binding protein 43 / TDP-43


Mass: 699.709 Da / Num. of mol.: 1 / Fragment: UNP residues 312-317 / Mutation: A315E / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: Q13148
#2: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: ELECTRON CRYSTALLOGRAPHY
EM experimentAggregation state: 3D ARRAY / 3D reconstruction method: electron crystallography

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Sample preparation

ComponentName: Segment from TDP-43 / Type: ORGANELLE OR CELLULAR COMPONENT / Entity ID: #1 / Source: NATURAL
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5 / Details: 1x PBS, pH 7.5
Buffer componentName: 1x PBS
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE
Crystal growTemperature: 298 K / Method: batch / pH: 7.5 / Details: 1x PBS, pH 7.5

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Data collection

Experimental equipment
Model: Tecnai F20 / Image courtesy: FEI Company
MicroscopyModel: FEI TECNAI F20
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: DIFFRACTION
Specimen holderCryogen: NITROGEN
Specimen holder model: GATAN 626 SINGLE TILT LIQUID NITROGEN CRYO TRANSFER HOLDER
Image recordingElectron dose: 3.4 e/Å2 / Film or detector model: TVIPS TEMCAM-F416 (4k x 4k)
Image scansWidth: 2048 / Height: 2048
EM diffractionCamera length: 1840 mm
EM diffraction shellResolution: 1→1.03 Å / Fourier space coverage: 78 % / Multiplicity: 4.8 / Num. of structure factors: 110 / Phase residual: 0.001 °
EM diffraction statsFourier space coverage: 88.7 % / High resolution: 1 Å / Num. of intensities measured: 18942 / Num. of structure factors: 2032 / Phase error: 0.001 ° / Phase residual: 0.001 ° / Phase error rejection criteria: 1 / Rmerge: 28.3 / Rsym: 28.3
DiffractionMean temperature: 100 K
Diffraction sourceSource: ELECTRON MICROSCOPE / Type: TECNAI F20 TEM / Wavelength: 0.0251 Å
DetectorType: TVIPS F416 CMOS CAMERA / Detector: CMOS / Date: Aug 26, 2016
Radiation wavelengthWavelength: 0.0251 Å / Relative weight: 1
ReflectionResolution: 1→21.39 Å / Num. obs: 2004 / % possible obs: 88.7 % / Observed criterion σ(I): -3 / Redundancy: 9.452 % / Biso Wilson estimate: 7.454 Å2 / CC1/2: 0.992 / Rmerge(I) obs: 0.283 / Rrim(I) all: 0.299 / Χ2: 0.775 / Net I/σ(I): 4.64 / Num. measured all: 18942 / Scaling rejects: 6
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsRrim(I) all% possible allCC1/2
1-1.034.8090.9931.075291411101.08578
1.03-1.066.7910.7971.848761461290.85288.40.527
1.06-1.097.7050.7062.2210711561390.7589.10.597
1.09-1.128.2910.7792.1411691501410.824940.551
1.12-1.168.9550.6862.6512001501340.72589.30.696
1.16-1.29.6480.7282.6813701511420.766940.574
1.2-1.2510.5040.6553.3313131421250.685880.834
1.25-1.39.4810.6633.0710241191080.69990.80.637
1.3-1.369.9360.4714.0710831201090.49690.80.835
1.36-1.4210.7760.5393.9211531181070.56790.70.583
1.42-1.510.9070.4744.4611671181070.49690.70.827
1.5-1.5911.8040.3695.7313221261120.38788.90.866
1.59-1.711.5330.3426.421061102920.35890.20.935
1.7-1.8310.0380.3256.3480393800.343860.941
1.83-2.0110.6470.2428.3690595850.25489.50.924
2.01-2.25110.1889.8989191810.197890.976
2.25-2.5911.2190.20910.0381983730.22880.982
2.59-3.188.9610.15510.2345759510.16586.40.985
3.18-4.499.6040.15112.8650964530.1682.80.969
4.49-21.398.4620.10812.2722035260.11474.30.998

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Processing

Software
NameVersionClassificationNB
XSCALEdata scaling
REFMACrefinement
PDB_EXTRACT3.22data extraction
XDSdata reduction
EM software
IDNameCategory
1TVIPS F416 CMOS CAMERAimage acquisition
6Cootmodel fitting
8REFMACmodel refinement
9SHELXDmolecular replacement
12XSCALEcrystallography merging
EM 3D crystal entity∠α: 90 ° / ∠β: 90 ° / ∠γ: 90 ° / A: 42.77 Å / B: 17.42 Å / C: 4.9 Å / Space group name: P21212 / Space group num: 18
CTF correctionType: NONE
3D reconstructionResolution: 1 Å / Resolution method: DIFFRACTION PATTERN/LAYERLINES / Symmetry type: 3D CRYSTAL
RefinementMethod to determine structure: AB INITIO PHASING / Resolution: 1→21.39 Å / Cor.coef. Fo:Fc: 0.958 / Cor.coef. Fo:Fc free: 0.913 / SU B: 2.368 / SU ML: 0.052 / SU R Cruickshank DPI: 0.0471 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.047 / ESU R Free: 0.05 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2697 203 10.1 %RANDOM
Rwork0.2201 ---
obs0.2251 1801 88.71 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 25.32 Å2 / Biso mean: 5.061 Å2 / Biso min: 2.59 Å2
Baniso -1Baniso -2Baniso -3
1-0.18 Å20 Å20 Å2
2--0.16 Å2-0 Å2
3----0.34 Å2
Refinement stepCycle: final / Resolution: 1→21.39 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms50 0 0 2 52
Biso mean---25.28 -
Num. residues----6
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
ELECTRON CRYSTALLOGRAPHYr_bond_refined_d0.0160.0251
ELECTRON CRYSTALLOGRAPHYr_bond_other_d0.0020.0237
ELECTRON CRYSTALLOGRAPHYr_angle_refined_deg1.0851.89667
ELECTRON CRYSTALLOGRAPHYr_angle_other_deg0.911386
ELECTRON CRYSTALLOGRAPHYr_dihedral_angle_1_deg7.06855
ELECTRON CRYSTALLOGRAPHYr_dihedral_angle_2_deg27.684254
ELECTRON CRYSTALLOGRAPHYr_dihedral_angle_3_deg7.324156
ELECTRON CRYSTALLOGRAPHYr_chiral_restr0.1350.25
ELECTRON CRYSTALLOGRAPHYr_gen_planes_refined0.0070.0261
ELECTRON CRYSTALLOGRAPHYr_gen_planes_other00.0215
ELECTRON CRYSTALLOGRAPHYr_rigid_bond_restr1.516387
ELECTRON CRYSTALLOGRAPHYr_sphericity_free25.53952
ELECTRON CRYSTALLOGRAPHYr_sphericity_bonded3.846587
LS refinement shellResolution: 1.005→1.031 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.323 11 -
Rwork0.35 99 -
all-110 -
obs--78.01 %

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