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- PDB-6cfh: SWGMMGMLASQ segment from the low complexity domain of TDP-43 -

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Basic information

Entry
Database: PDB / ID: 6cfh
TitleSWGMMGMLASQ segment from the low complexity domain of TDP-43
ComponentsTAR DNA-binding protein 43
KeywordsPROTEIN FIBRIL / Amyloid / steric zipper
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 non-membrane-bounded organelle / negative regulation by host of viral transcription / pre-mRNA intronic binding / molecular condensate scaffold activity / response to endoplasmic reticulum stress ...nuclear inner membrane organization / interchromatin granule / perichromatin fibrils / 3'-UTR-mediated mRNA destabilization / 3'-UTR-mediated mRNA stabilization / intracellular non-membrane-bounded organelle / negative regulation by host of viral transcription / pre-mRNA intronic binding / molecular condensate scaffold activity / response to endoplasmic reticulum stress / RNA splicing / negative regulation of protein phosphorylation / mRNA 3'-UTR binding / regulation of protein stability / regulation of circadian rhythm / positive regulation of insulin secretion / mRNA processing / cytoplasmic stress granule / positive regulation of protein import into nucleus / rhythmic process / double-stranded DNA binding / regulation of gene expression / 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 / mitochondrion / DNA binding / RNA binding / nucleoplasm / identical protein binding / nucleus
Similarity search - Function
: / TAR DNA-binding protein 43, C-terminal / TAR DNA-binding protein 43, N-terminal / TAR DNA-binding protein 43, N-terminal domain / 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 / MOLECULAR REPLACEMENT / molecular replacement / cryo EM / Resolution: 1.5 Å
AuthorsGuenther, E.L. / Rodriguez, J.A. / 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 15, 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 17, 2020Group: Database references / Source and taxonomy / Structure summary
Category: entity / entity_name_com ...entity / entity_name_com / pdbx_entity_src_syn / struct_ref / struct_ref_seq
Item: _entity.pdbx_description / _entity.pdbx_fragment ..._entity.pdbx_description / _entity.pdbx_fragment / _pdbx_entity_src_syn.organism_common_name / _struct_ref.db_code / _struct_ref.db_name / _struct_ref.pdbx_align_begin / _struct_ref.pdbx_db_accession / _struct_ref.pdbx_seq_one_letter_code / _struct_ref_seq.pdbx_db_accession
Revision 1.5Jun 30, 2021Group: Data collection / Category: diffrn_detector / Item: _diffrn_detector.detector
Revision 1.6Oct 13, 2021Group: Database references / Refinement description
Category: database_2 / pdbx_refine_tls ...database_2 / pdbx_refine_tls / pdbx_refine_tls_group / refine / refine_hist
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_refine_tls.pdbx_refine_id / _pdbx_refine_tls_group.pdbx_refine_id / _refine_hist.pdbx_refine_id

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Structure visualization

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Assembly

Deposited unit
A: TAR DNA-binding protein 43
B: TAR DNA-binding protein 43


Theoretical massNumber of molelcules
Total (without water)2,3972
Polymers2,3972
Non-polymers00
Water0
1
A: TAR DNA-binding protein 43
B: TAR DNA-binding protein 43
x 10


Theoretical massNumber of molelcules
Total (without water)23,96920
Polymers23,96920
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation1_545x,y-1,z1
crystal symmetry operation1_565x,y+1,z1
crystal symmetry operation1_655x+1,y,z1
crystal symmetry operation1_645x+1,y-1,z1
crystal symmetry operation1_535x,y-2,z1
crystal symmetry operation1_575x,y+2,z1
crystal symmetry operation1_665x+1,y+1,z1
crystal symmetry operation1_635x+1,y-2,z1
crystal symmetry operation1_675x+1,y+2,z1
Unit cell
Length a, b, c (Å)8.560, 9.600, 39.970
Angle α, β, γ (deg.)97.170, 92.890, 105.940
Int Tables number1
Space group name H-MP1

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Components

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


Mass: 1198.436 Da / Num. of mol.: 2 / Fragment: SWGMMGMLASQ segment / Source method: obtained synthetically
Details: Synthetic peptide SWGMMGMLASQ corresponding tosegment 333-343 of TDP-43
Source: (synth.) Homo sapiens (human) / References: UniProt: Q13148

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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 SWGMMGMLASQ / Type: COMPLEX / Entity ID: all / 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 80 hours.
Lipid mixture: none / Temperature: 310 K / Time: 4 DAY
Buffer solutionpH: 7.5
Buffer component
IDNameBuffer-ID
1sodium chloride1
2potassium chloride1
3dibasic sodium phosphate1
4monobasic potassium phosphate1
SpecimenConc.: 24 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: crystal
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: 303 K / Method: batch / pH: 7.5 / Details: phosphate buffered saline, shaken for 80 hours

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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: 2 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 / Num. of real images: 891
Details: The detector was operated in rolling shutter mode with 2X2 pixel binning.
Image scansWidth: 4096 / Height: 4096
EM diffractionCamera length: 1850 mm
EM diffraction shellResolution: 1.5→13.1675 Å / Fourier space coverage: 93.5 % / Multiplicity: 4.2 / Num. of structure factors: 1819 / Phase residual: 55.72 °
EM diffraction statsFourier space coverage: 93.5 % / High resolution: 1.5 Å / Num. of intensities measured: 7695 / Num. of structure factors: 1819 / Phase error: 55.72 ° / Phase residual: 55.72 ° / Phase error rejection criteria: 0 / Rmerge: 20.8 / Rsym: 20.8
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: Aug 18, 2015
Radiation wavelengthWavelength: 0.0251 Å / Relative weight: 1
ReflectionResolution: 1.5→13.17 Å / Num. obs: 1819 / % possible obs: 93.5 % / Redundancy: 4.23 % / Biso Wilson estimate: 14.37 Å2 / CC1/2: 0.987 / Rmerge(I) obs: 0.208 / Rrim(I) all: 0.231 / Χ2: 0.955 / Net I/σ(I): 3.31 / Num. measured all: 7695 / Scaling rejects: 5
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
1.5-1.552.3690.8550.683981881680.721.09689.4
1.55-1.592.660.4891.163751571410.9620.61189.8
1.59-1.652.5160.7571.113221391280.570.95492.1
1.65-1.72.8930.5831.24051451400.7480.70296.6
1.7-1.773.1970.6641.443901311220.6170.79493.1
1.77-1.843.6330.531.84651391280.8850.61192.1
1.84-1.925.0810.4052.586301321240.970.44993.9
1.92-2.025.1880.2793.975241081010.9540.30993.5
2.02-2.135.0870.3093.556411351260.9690.34593.3
2.13-2.255.680.2434.795681001000.9870.267100
2.25-2.416.0780.2085.086261051030.9930.22798.1
2.41-2.65.3050.3263.8343587820.9770.36594.3
2.6-2.855.170.2245.165171051000.9920.25395.2
2.85-3.195.9440.2316.3742874720.9830.25497.3
3.19-3.685.2270.1727.9634571660.9840.1993
3.68-4.515.40.179.2129761550.9830.18790.2
4.51-6.385.1580.1349.2919639380.9830.14697.4
6.38-13.175.320.1327.4313329250.9970.14786.2

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation1.5 Å13.17 Å
Translation1.5 Å13.17 Å

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Processing

Software
NameVersionClassificationNB
XDSdata reduction
XSCALEdata scaling
PHASER2.7.17phasing
BUSTER2.10.3refinement
PDB_EXTRACT3.24data extraction
EM software
IDNameVersionCategory
1EM-Menuimage acquisition
6Coot0.8.9model fitting
13BUSTER2.10.3model refinement
EM 3D crystal entity∠α: 97.171 ° / ∠β: 92.895 ° / ∠γ: 105.943 ° / A: 8.56 Å / B: 9.6 Å / C: 39.97 Å / Space group name: P1 / Space group num: 1
CTF correctionType: NONE
3D reconstructionResolution method: DIFFRACTION PATTERN/LAYERLINES
Details: Density map was obtained using measured diffraction intensities and phases acquired from a molecular replacement program, phaser.
Symmetry type: 3D CRYSTAL
Atomic model buildingB value: 17.4 / Protocol: OTHER / Space: RECIPROCAL / Target criteria: maximum likihood
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.5→13.17 Å / Cor.coef. Fo:Fc: 0.908 / Cor.coef. Fo:Fc free: 0.889 / SU R Cruickshank DPI: 0.231 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.155 / SU Rfree Blow DPI: 0.139 / SU Rfree Cruickshank DPI: 0.141
RfactorNum. reflection% reflectionSelection details
Rfree0.313 182 10.01 %RANDOM
Rwork0.28 ---
obs0.283 1819 93.1 %-
Displacement parametersBiso max: 56.35 Å2 / Biso mean: 18.14 Å2 / Biso min: 4.51 Å2
Baniso -1Baniso -2Baniso -3
1--2.3572 Å2-0.8318 Å2-1.5911 Å2
2--0.5881 Å20.4244 Å2
3---1.7692 Å2
Refine analyzeLuzzati coordinate error obs: 0.39 Å
Refinement stepCycle: final / Resolution: 1.5→13.17 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms161 0 0 0 161
Num. residues----22
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
ELECTRON CRYSTALLOGRAPHYt_dihedral_angle_d62SINUSOIDAL2
ELECTRON CRYSTALLOGRAPHYt_trig_c_planes4HARMONIC2
ELECTRON CRYSTALLOGRAPHYt_gen_planes44HARMONIC5
ELECTRON CRYSTALLOGRAPHYt_it318HARMONIC20
ELECTRON CRYSTALLOGRAPHYt_nbd4SEMIHARMONIC5
ELECTRON CRYSTALLOGRAPHYt_improper_torsion
ELECTRON CRYSTALLOGRAPHYt_pseud_angle
ELECTRON CRYSTALLOGRAPHYt_chiral_improper_torsion18SEMIHARMONIC5
ELECTRON CRYSTALLOGRAPHYt_sum_occupancies
ELECTRON CRYSTALLOGRAPHYt_utility_distance
ELECTRON CRYSTALLOGRAPHYt_utility_angle
ELECTRON CRYSTALLOGRAPHYt_utility_torsion
ELECTRON CRYSTALLOGRAPHYt_ideal_dist_contact382SEMIHARMONIC4
ELECTRON CRYSTALLOGRAPHYt_bond_d318HARMONIC20.007
ELECTRON CRYSTALLOGRAPHYt_angle_deg564HARMONIC20.91
ELECTRON CRYSTALLOGRAPHYt_omega_torsion1.69
ELECTRON CRYSTALLOGRAPHYt_other_torsion19.15
LS refinement shellResolution: 1.5→1.68 Å / Rfactor Rfree error: 0 / Total num. of bins used: 5
RfactorNum. reflection% reflection
Rfree0.2387 51 10 %
Rwork0.2178 459 -
all0.2199 510 -
obs--89.32 %
Refinement TLS params.

Method: refined / Refine-ID: ELECTRON CRYSTALLOGRAPHY

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.44460.15530.25830.7719-0.00290.1413-0.01770.015-0.01930.03450.02140.01-0.00120.0081-0.00360.01230.0212-0.0136-0.05840.0207-0.00251.5567-1.5678.5522
20.175-0.3835-0.26771.04780.22120.2632-0.0069-0.01330.0326-0.00480.0206-0.0360.0040.0056-0.0137-0.00340.05240.0033-0.0112-0.0393-0.05780.07232.93658.5141
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1ELECTRON CRYSTALLOGRAPHY1{A|333 - 343}A333 - 343
2ELECTRON CRYSTALLOGRAPHY2{B|333 - 343}B333 - 343

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