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- PDB-5whp: Crystal structure of the segment, NFGTFS, from the A315T familial... -

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Basic information

Entry
Database: PDB / ID: 5whp
TitleCrystal structure of the segment, NFGTFS, from the A315T familial variant of the low complexity domain of TDP-43, residues 312-317
ComponentsSegment of TAR 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 non-membrane-bounded organelle / negative regulation by host of viral transcription / pre-mRNA intronic binding / response to endoplasmic reticulum stress / RNA splicing ...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 / response to endoplasmic reticulum stress / RNA splicing / negative regulation of protein phosphorylation / molecular condensate scaffold activity / mRNA 3'-UTR binding / regulation of protein stability / regulation of circadian rhythm / positive regulation of insulin secretion / mRNA processing / positive regulation of protein import into nucleus / 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 / 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)
MethodX-RAY DIFFRACTION / SYNCHROTRON / AB INITIO PHASING / Resolution: 1 Å
AuthorsGuenther, E.L. / Sawaya, M.R. / 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 17, 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.pdbx_database_id_DOI / _citation.title / _citation.year
Revision 1.2Jun 6, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.pdbx_database_id_PubMed ..._citation.journal_abbrev / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
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 1.5Jan 15, 2020Group: Data collection / Category: reflns_shell / Item: _reflns_shell.percent_possible_all
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

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Segment of TAR DNA-binding protein 43


Theoretical massNumber of molelcules
Total (without water)6721
Polymers6721
Non-polymers00
Water543
1
A: Segment of TAR DNA-binding protein 43
x 10


Theoretical massNumber of molelcules
Total (without water)6,71710
Polymers6,71710
Non-polymers00
Water18010
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation1_535x,y-2,z1
crystal symmetry operation1_545x,y-1,z1
crystal symmetry operation1_565x,y+1,z1
crystal symmetry operation1_575x,y+2,z1
crystal symmetry operation2_625-x+1,y-5/2,-z1
crystal symmetry operation2_635-x+1,y-3/2,-z1
crystal symmetry operation2_645-x+1,y-1/2,-z1
crystal symmetry operation2_655-x+1,y+1/2,-z1
crystal symmetry operation2_665-x+1,y+3/2,-z1
Unit cell
Length a, b, c (Å)15.330, 4.840, 23.570
Angle α, β, γ (deg.)90.000, 96.910, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 671.699 Da / Num. of mol.: 1 / Fragment: UNP residues 312-317 / Mutation: A315T / Source method: obtained synthetically
Details: Synthetic peptide NFGTFS corresponding tosegment 312-317 of TDP-43
Source: (synth.) Homo sapiens (human) / References: UniProt: Q13148
#2: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 3 / 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

Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 4.6
Details: 100mM sodium acetate 4.6, 200mM ammonium acetate, 30% PEG 4000

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.9791 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Oct 16, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9791 Å / Relative weight: 1
ReflectionResolution: 1→15.22 Å / Num. obs: 1823 / % possible obs: 87.6 % / Observed criterion σ(I): -3 / Redundancy: 4.918 % / Biso Wilson estimate: 4.863 Å2 / CC1/2: 0.993 / Rmerge(I) obs: 0.086 / Rrim(I) all: 0.096 / Χ2: 0.959 / Net I/σ(I): 14.97
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsCC1/2Rrim(I) all% possible all
1-1.032.8420.1047.59570.980.12537
1.03-1.063.2780.0918.94900.9910.10856.6
1.06-1.13.3870.08710.821060.9890.10371.1
1.1-1.144.2620.10412.571490.9890.11895.5
1.14-1.184.8660.10613.841570.9880.11999.4
1.18-1.235.3660.09714.651310.9930.10692.9
1.23-1.285.5910.09415.41270.990.103100
1.28-1.345.5910.08816.091270.9910.098100
1.34-1.425.4220.086151280.9950.09699.2
1.42-1.55.4840.08716.681240.9920.097100
1.5-1.615.2620.07716.731220.9930.086100
1.61-1.735.5820.08817.47910.9950.09798.9
1.73-1.95.5730.08517.93960.9940.093100
1.9-2.125.4220.08717.98900.9890.095100
2.12-2.455.0880.08517.97910.9870.09597.8
2.45-34.9380.07218650.9920.08297
3-4.254.490.07517.04490.9890.08581.7
4.25-15.223.3480.06814.57230.9890.08362.2

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Processing

Software
NameVersionClassification
XSCALEdata scaling
REFMAC5.7.0032refinement
PDB_EXTRACT3.22data extraction
SHELXDphasing
XDSdata reduction
RefinementMethod to determine structure: AB INITIO PHASING / Resolution: 1→15.22 Å / Cor.coef. Fo:Fc: 0.986 / Cor.coef. Fo:Fc free: 0.983 / SU B: 0.436 / SU ML: 0.01 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.02 / ESU R Free: 0.018
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.0929 183 10 %RANDOM
Rwork0.0866 ---
obs0.0873 1639 87.68 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 36.25 Å2 / Biso mean: 2.626 Å2 / Biso min: 2 Å2
Baniso -1Baniso -2Baniso -3
1-0.19 Å2-0 Å2-0.17 Å2
2--0.07 Å20 Å2
3----0.23 Å2
Refinement stepCycle: final / Resolution: 1→15.22 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms48 0 0 3 51
Biso mean---14.75 -
Num. residues----6
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0190.0249
X-RAY DIFFRACTIONr_bond_other_d0.0010.0239
X-RAY DIFFRACTIONr_angle_refined_deg1.791.87465
X-RAY DIFFRACTIONr_angle_other_deg0.687388
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.21255
X-RAY DIFFRACTIONr_dihedral_angle_2_deg14.00723.3333
X-RAY DIFFRACTIONr_dihedral_angle_3_deg8.865155
X-RAY DIFFRACTIONr_chiral_restr0.1320.26
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0259
X-RAY DIFFRACTIONr_gen_planes_other0.0010.0217
X-RAY DIFFRACTIONr_rigid_bond_restr5.773388
X-RAY DIFFRACTIONr_sphericity_bonded2.03590
LS refinement shellResolution: 1.002→1.028 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.187 5 -
Rwork0.132 42 -
all-47 -
obs--35.07 %

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