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- PDB-6cf4: Segment NFGTFS, with familial mutation A315T and phosphorylated t... -

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Basic information

Entry
Database: PDB / ID: 6cf4
TitleSegment NFGTFS, with familial mutation A315T and phosphorylated threonine, from the low complexity domain of TDP-43, residues 312-317
ComponentsNFGTFS
KeywordsPROTEIN FIBRIL / Amyloid / LARKS / Reversible aggregation
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 / regulation of circadian rhythm / positive regulation of insulin secretion / 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 / cryo EM / Resolution: 0.75 Å
AuthorsGuenther, E.L. / Cao, Q. / Boyer, D.R. / Sawaya, M.R. / Eisenberg, D.S.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute on Aging (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
DepositionFeb 13, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 23, 2018Provider: repository / Type: Initial release
Revision 1.1Jun 6, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Jun 13, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Dec 18, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Jun 30, 2021Group: Data collection / Category: diffrn_detector / Item: _diffrn_detector.detector
Revision 1.5Nov 6, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _em_admin.last_update

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Structure visualization

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Assembly

Deposited unit
A: NFGTFS


Theoretical massNumber of molelcules
Total (without water)7521
Polymers7521
Non-polymers00
Water181
1
A: NFGTFS
x 10


Theoretical massNumber of molelcules
Total (without water)7,51710
Polymers7,51710
Non-polymers00
Water18010
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation1_565x,y+1,z1
crystal symmetry operation1_575x,y+2,z1
crystal symmetry operation1_545x,y-1,z1
crystal symmetry operation1_535x,y-2,z1
crystal symmetry operation3_565-x,y+3/2,-z+1/21
crystal symmetry operation3_555-x,y+1/2,-z+1/21
crystal symmetry operation3_545-x,y-1/2,-z+1/21
crystal symmetry operation3_535-x,y-3/2,-z+1/21
crystal symmetry operation3_525-x,y-5/2,-z+1/21
Unit cell
Length a, b, c (Å)23.650, 4.720, 30.060
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein/peptide NFGTFS


Mass: 751.679 Da / Num. of mol.: 1 / Source method: obtained synthetically
Details: Synthetic peptide NFGpTFS corresponding tosegment 312-317 of TDP-43, with phosphorylated threonine
Source: (synth.) Homo sapiens (human) / References: UniProt: Q13148*PLUS
#2: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: crystal of NFGTFS phosphorylated on threonine. / Type: COMPLEX / Entity ID: #1 / Source: NATURAL
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
EM crystal formationInstrument: microcentrifuge tube / Atmosphere: air, sealed chamber
Details: Crystals were prepared by shaking peptide in microcentrifuge tube at 37 deg Celsius for 4 days.
Lipid mixture: none / Temperature: 310 K / Time: 4 DAY
Buffer solutionpH: 4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R2/2
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE
Crystal growTemperature: 310 K / Method: batch / pH: 7.5 / Details: 1X PBS 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 / Alignment procedure: BASIC
Specimen holderCryogen: NITROGEN
Specimen holder model: GATAN 626 SINGLE TILT LIQUID NITROGEN CRYO TRANSFER HOLDER
Temperature (max): 100 K / Temperature (min): 100 K
Image recordingAverage exposure time: 3 sec. / Electron dose: 0.01 e/Å2 / Film or detector model: TVIPS TEMCAM-F416 (4k x 4k) / Num. of diffraction images: 100 / Num. of grids imaged: 1
Details: The detector was operated in rolling shutter mode with 2X2 pixel binning.
Image scansWidth: 4096 / Height: 4096
EM diffractionCamera length: 819 mm
EM diffraction shell
Resolution (Å)IDEM diffraction stats-IDFourier space coverage (%)MultiplicityNum. of structure factorsPhase residual (°)
7.65-1.0811853.6130020.96
1.08-0.8621883.9124137.03
0.86-0.7531883.9120939.38
EM diffraction statsFourier space coverage: 86.6 % / High resolution: 0.75 Å / Num. of intensities measured: 15891 / Num. of structure factors: 4177 / Phase error: 32.2 ° / Phase residual: 32.2 ° / Phase error rejection criteria: 0 / Rmerge: 17.2 / Rsym: 17.2
DiffractionMean temperature: 100 K
Diffraction sourceSource: TRANSMISSION ELECTRON MICROSCOPE / Type: TECNAI F20 TEM / Wavelength: 0.0251 Å
DetectorType: TVIPS F416 CMOS CAMERA / Detector: CMOS / Date: Jan 9, 2018
Radiation wavelengthWavelength: 0.0251 Å / Relative weight: 1
ReflectionResolution: 0.75→7.645 Å / Num. obs: 4177 / % possible obs: 86.6 % / Redundancy: 3.804 % / Biso Wilson estimate: 40.55 Å2 / CC1/2: 0.989 / Rmerge(I) obs: 0.172 / Rrim(I) all: 0.203 / Χ2: 0.958 / Net I/σ(I): 3.9 / Num. measured all: 15891
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsCC1/2Rrim(I) all% possible all
0.75-0.774.010.6611.2812593603140.5990.75787.2
0.77-0.794.10.6681.4312713523100.5330.7788.1
0.79-0.813.6340.6561.359743062680.4740.77287.6
0.81-0.843.8450.6331.5310193012650.6250.7388
0.84-0.873.9240.5591.8310323032630.6460.64586.8
0.87-0.94.0370.422.5810823052680.7880.48487.9
0.9-0.934.2440.3023.4811463062700.9030.34188.2
0.93-0.973.6930.3043.369012772440.8640.35388.1
0.97-1.013.6070.3413.378082582240.8320.40586.8
1.01-1.063.830.2734.488352512180.8720.3286.9
1.06-1.124.0180.2145.199122592270.9690.24787.6
1.12-1.194.1220.2135.719152532220.9530.24887.7
1.19-1.273.3890.1775.615932081750.9580.21184.1
1.27-1.373.3540.25.485972041780.9420.23987.3
1.37-1.53.8870.1846.76882071770.9290.21685.5
1.5-1.683.6730.1517.215731791560.9290.18187.2
1.68-1.943.0080.1437.093821521270.9290.17483.6
1.94-2.373.7690.1298.655051611340.9760.1583.2
2.37-3.362.9150.0828.71239102820.9830.10280.4
3.36-7.6452.9090.0689.5516078550.9910.08270.5

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Processing

Software
NameVersionClassificationNB
XDSdata reduction
XSCALEdata scaling
PHENIXrefinement
PDB_EXTRACT3.24data extraction
EM software
IDNameVersionCategoryDetails
1EM-Menuimage acquisition
6Cootmodel fitting
12SHELXD2013/23D reconstructiondirect methods
13PHENIXmodel refinement
EM 3D crystal entity∠α: 90 ° / ∠β: 90 ° / ∠γ: 90 ° / A: 23.65 Å / B: 4.72 Å / C: 30.06 Å / Space group name: P212121 / Space group num: 19
CTF correctionType: NONE
3D reconstructionResolution method: DIFFRACTION PATTERN/LAYERLINES
Details: Density map was obtained using measured diffraction intensities and phases acquired from a crystallographic direct methods program, shelxd.
Symmetry type: 3D CRYSTAL
Atomic model buildingB value: 19.6 / Protocol: OTHER / Space: RECIPROCAL / Target criteria: maximum likihood
RefinementResolution: 0.75→7.645 Å / SU ML: 0.11 / Cross valid method: THROUGHOUT / σ(F): 1.38 / Phase error: 30.21
RfactorNum. reflection% reflection
Rfree0.2512 428 10.24 %
Rwork0.2324 --
obs0.2346 4178 86.77 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 170.86 Å2 / Biso mean: 12.108 Å2 / Biso min: 0 Å2
Refinement stepCycle: final / Resolution: 0.75→7.645 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms52 0 0 1 53
Biso mean---3.07 -
Num. residues----6
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON CRYSTALLOGRAPHYf_bond_d0.02153
ELECTRON CRYSTALLOGRAPHYf_angle_d2.04272
ELECTRON CRYSTALLOGRAPHYf_chiral_restr0.116
ELECTRON CRYSTALLOGRAPHYf_plane_restr0.0089
ELECTRON CRYSTALLOGRAPHYf_dihedral_angle_d32.516
LS refinement shell

Refine-ID: ELECTRON CRYSTALLOGRAPHY / Rfactor Rfree error: 0 / Total num. of bins used: 3

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
0.7503-0.85880.40231390.38191209134888
0.8588-1.08150.27741370.28281241137888
1.0815-7.6450.20981520.18611300145285

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