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- PDB-6cew: Segment AMMAAA from the low complexity domain of TDP-43, residues... -

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Basic information

Entry
Database: PDB / ID: 6cew
TitleSegment AMMAAA from the low complexity domain of TDP-43, residues 321-326
ComponentsAMMAAA
KeywordsPROTEIN FIBRIL / Amyloid / Steric-zipper
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.2 Å
AuthorsGuenther, E.L. / Cao, Q. / Lu, J. / 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 12, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 18, 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_DOI ..._citation.journal_abbrev / _citation.pdbx_database_id_DOI / _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 1.4Mar 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
Revision 1.5Apr 3, 2024Group: Refinement description / Category: pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: AMMAAA
B: AMMAAA


Theoretical massNumber of molelcules
Total (without water)1,1292
Polymers1,1292
Non-polymers00
Water724
1
A: AMMAAA
B: AMMAAA
x 6


Theoretical massNumber of molelcules
Total (without water)6,77712
Polymers6,77712
Non-polymers00
Water1086
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation1_455x-1,y,z1
crystal symmetry operation1_655x+1,y,z1
crystal symmetry operation4_555x+1/2,-y+1/2,-z1
crystal symmetry operation4_455x-1/2,-y+1/2,-z1
crystal symmetry operation4_655x+3/2,-y+1/2,-z1
Unit cell
Length a, b, c (Å)9.520, 15.440, 44.100
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 AMMAAA


Mass: 564.718 Da / Num. of mol.: 2 / Fragment: residues 321-326 / Source method: obtained synthetically
Details: Synthetic peptide AMMAAA corresponding to segment 321-326 of TDP-43
Source: (synth.) Homo sapiens (human)
#2: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 4 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 1.43 Å3/Da
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 6.3
Details: 1.3 M ammonium phosphate, 0.1 M sodium acetate pH 6.3

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.9791 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Dec 1, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9791 Å / Relative weight: 1
ReflectionResolution: 1.2→22.05 Å / Num. obs: 2209 / % possible obs: 96 % / Redundancy: 3.507 % / Biso Wilson estimate: 12.836 Å2 / CC1/2: 0.995 / Rmerge(I) obs: 0.181 / Rrim(I) all: 0.214 / Χ2: 0.781 / Net I/σ(I): 3.16
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsCC1/2Rrim(I) all% possible all
1.2-1.233.4970.6831.431450.6920.899.3
1.23-1.273.60.6171.621550.8860.72299.4
1.27-1.33.390.5791.571540.8440.67792.8
1.3-1.343.6240.4841.921250.8890.55988
1.34-1.393.7920.4412.331440.8190.51792.9
1.39-1.443.8580.5362.111340.8090.62199.3
1.44-1.493.6180.3672.531360.940.4398.6
1.49-1.553.5150.3572.711340.940.41595
1.55-1.623.6420.3442.81200.8960.40190.2
1.62-1.73.5860.2493.521110.9810.29797.4
1.7-1.793.3130.263.671150.9830.30393.5
1.79-1.93.4740.2374.141140.9730.27795
1.9-2.033.7250.2274.221020.9380.26397.1
2.03-2.193.5730.1794.57960.9690.20599
2.19-2.43.2290.1855.02960.9620.22198
2.4-2.693.4320.174.92810.9530.20998.8
2.69-3.13.1590.1315.44820.9470.15898.8
3.1-3.83.2740.1245.62620.9740.14495.4
3.8-5.373.0630.1035.87630.9970.126100
5.37-22.052.60.0314.484010.038100

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation1.53 Å22.08 Å
Translation1.53 Å22.08 Å

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Processing

Software
NameVersionClassificationNB
XDSdata reduction
XSCALEdata scaling
PHASER2.7.17phasing
REFMACrefinement
PDB_EXTRACT3.24data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: IDEAL BETA STRAND

Resolution: 1.2→22.05 Å / Cor.coef. Fo:Fc: 0.929 / Cor.coef. Fo:Fc free: 0.955 / SU B: 2.286 / SU ML: 0.045 / SU R Cruickshank DPI: 0.0612 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.061 / ESU R Free: 0.054
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2184 108 4.9 %RANDOM
Rwork0.1979 ---
obs0.1989 2078 96.09 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 25.38 Å2 / Biso mean: 9.425 Å2 / Biso min: 6.16 Å2
Baniso -1Baniso -2Baniso -3
1--0.64 Å20 Å2-0 Å2
2--0.85 Å20 Å2
3----0.21 Å2
Refinement stepCycle: final / Resolution: 1.2→22.05 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms74 0 0 4 78
Biso mean---22.32 -
Num. residues----12
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0278
X-RAY DIFFRACTIONr_bond_other_d0.0020.0288
X-RAY DIFFRACTIONr_angle_refined_deg1.4312.028103
X-RAY DIFFRACTIONr_angle_other_deg0.6293200
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.912512
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.1271515
X-RAY DIFFRACTIONr_chiral_restr0.0580.213
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.0285
X-RAY DIFFRACTIONr_gen_planes_other0.0010.0211
X-RAY DIFFRACTIONr_rigid_bond_restr2.0793166
X-RAY DIFFRACTIONr_sphericity_free20.46453
X-RAY DIFFRACTIONr_sphericity_bonded3.6265168
LS refinement shellResolution: 1.201→1.232 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.261 12 -
Rwork0.261 133 -
all-145 -
obs--98.64 %

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