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- PDB-7vi4: Electron crystallographic structure of TIA-1 prion-like domain, A... -

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Basic information

Entry
Database: PDB / ID: 7vi4
TitleElectron crystallographic structure of TIA-1 prion-like domain, A381T mutant
ComponentsTIA-1 prion-like domain
KeywordsPROTEIN FIBRIL / ALS / prion / fibril
Function / homology
Function and homology information


protein localization to cytoplasmic stress granule / nuclear stress granule / mRNA 3'-UTR AU-rich region binding / poly(A) binding / regulation of mRNA splicing, via spliceosome / positive regulation of epithelial cell apoptotic process / FGFR2 alternative splicing / negative regulation of cytokine production / regulation of alternative mRNA splicing, via spliceosome / stress granule assembly ...protein localization to cytoplasmic stress granule / nuclear stress granule / mRNA 3'-UTR AU-rich region binding / poly(A) binding / regulation of mRNA splicing, via spliceosome / positive regulation of epithelial cell apoptotic process / FGFR2 alternative splicing / negative regulation of cytokine production / regulation of alternative mRNA splicing, via spliceosome / stress granule assembly / RNA splicing / mRNA 3'-UTR binding / cytoplasmic stress granule / mRNA processing / negative regulation of translation / ribonucleoprotein complex / apoptotic process / RNA binding / nucleoplasm / nucleus / cytosol / cytoplasm
Similarity search - Function
TIA-1, RNA recognition motif 1 / TIA-1, RNA recognition motif 2 / TIAR, RNA recognition motif 3 / RNA recognition motif domain, eukaryote / RNA recognition motif / 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
Cytotoxic granule associated RNA binding protein TIA1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON CRYSTALLOGRAPHY / electron crystallography / Resolution: 0.95 Å
AuthorsTakaba, K. / Maki-Yonekura, S. / Sekiyama, N. / Imamura, K. / Kodama, T. / Tochio, H. / Yonekura, K.
Funding support Japan, 5items
OrganizationGrant numberCountry
Japan Society for the Promotion of Science (JSPS)JP19K06584 Japan
Japan Science and TechnologyJPMJCR1762 Japan
Japan Science and TechnologyJPMJMI20G5 Japan
Ministry of Education, Culture, Sports, Science and Technology (Japan)JPMXS0421700121 Japan
Japan Agency for Medical Research and Development (AMED) Japan
CitationJournal: Proc Natl Acad Sci U S A / Year: 2022
Title: ALS mutations in the TIA-1 prion-like domain trigger highly condensed pathogenic structures.
Authors: Naotaka Sekiyama / Kiyofumi Takaba / Saori Maki-Yonekura / Ken-Ichi Akagi / Yasuko Ohtani / Kayo Imamura / Tsuyoshi Terakawa / Keitaro Yamashita / Daigo Inaoka / Koji Yonekura / Takashi S ...Authors: Naotaka Sekiyama / Kiyofumi Takaba / Saori Maki-Yonekura / Ken-Ichi Akagi / Yasuko Ohtani / Kayo Imamura / Tsuyoshi Terakawa / Keitaro Yamashita / Daigo Inaoka / Koji Yonekura / Takashi S Kodama / Hidehito Tochio /
Abstract: T cell intracellular antigen-1 (TIA-1) plays a central role in stress granule (SG) formation by self-assembly via the prion-like domain (PLD). In the TIA-1 PLD, amino acid mutations associated with ...T cell intracellular antigen-1 (TIA-1) plays a central role in stress granule (SG) formation by self-assembly via the prion-like domain (PLD). In the TIA-1 PLD, amino acid mutations associated with neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) or Welander distal myopathy (WDM), have been identified. However, how these mutations affect PLD self-assembly properties has remained elusive. In this study, we uncovered the implicit pathogenic structures caused by the mutations. NMR analysis indicated that the dynamic structures of the PLD are synergistically determined by the physicochemical properties of amino acids in units of five residues. Molecular dynamics simulations and three-dimensional electron crystallography, together with biochemical assays, revealed that the WDM mutation E384K attenuated the sticky properties, whereas the ALS mutations P362L and A381T enhanced the self-assembly by inducing β-sheet interactions and highly condensed assembly, respectively. These results suggest that the P362L and A381T mutations increase the likelihood of irreversible amyloid fibrillization after phase-separated droplet formation, and this process may lead to pathogenicity.
History
DepositionSep 24, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Sep 28, 2022Provider: repository / Type: Initial release
Revision 1.1Jun 19, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Structure visualization

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Assembly

Deposited unit
A: TIA-1 prion-like domain


Theoretical massNumber of molelcules
Total (without water)1,1741
Polymers1,1741
Non-polymers00
Water543
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)30.680, 9.630, 26.250
Angle α, β, γ (deg.)90.000, 116.150, 90.000
Int Tables number5
Space group name H-MC121

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Components

#1: Protein/peptide TIA-1 prion-like domain / RNA-binding protein TIA-1 / T-cell-restricted intracellular antigen-1 / TIA-1 / p40-TIA-1


Mass: 1174.241 Da / Num. of mol.: 1 / Mutation: A381T / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P31483
#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: ELECTRON CRYSTALLOGRAPHY
EM experimentAggregation state: FILAMENT / 3D reconstruction method: electron crystallography

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Sample preparation

ComponentName: Region 2 peptides (G377-A386) of TIA-1 prion-like domain, A381T
Type: CELL / Entity ID: #1 / Source: NATURAL
Source (natural)Organism: synthetic construct (others)
Buffer solutionpH: 7.5
Buffer component
IDConc.NameFormulaBuffer-ID
10.2 Mammonium phosphate(NH4)2HPO41
240 %MPDC6H14O21
30.1 MHEPESC8H18N2O4S1
SpecimenConc.: 10 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: NO
Specimen supportGrid material: COPPER / Grid mesh size: 200 divisions/in. / Grid type: Quantifoil R1.2/1.3

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Data collection

MicroscopyModel: JEOL CRYO ARM 300
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: DIFFRACTION
Image recordingAverage exposure time: 1 sec. / Electron dose: 0.02 e/Å2 / Detector mode: INTEGRATING / Film or detector model: DIRECT ELECTRON DE-64 (8k x 8k)
Image scansSampling size: 6.5 µm / Width: 4096 / Height: 4096 / Movie frames/image: 20
EM diffractionCamera length: 1060 mm
EM diffraction shellResolution: 0.95→15.1 Å / Fourier space coverage: 77.7 % / Multiplicity: 27 / Num. of structure factors: 3555 / Phase residual: 34.66 °
EM diffraction statsFourier space coverage: 77.7 % / High resolution: 0.95 Å / Num. of intensities measured: 95985 / Num. of structure factors: 3555 / Phase error rejection criteria: None / Rmerge: 37.3

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Processing

Software
NameVersionClassificationNB
PHENIX1.12_2829refinement
PDB_EXTRACT3.27data extraction
EM 3D crystal entity∠α: 90 ° / ∠β: 116.15 ° / ∠γ: 90 ° / A: 30.68 Å / B: 9.63 Å / C: 26.25 Å / Space group name: C2 / Space group num: 5
CTF correctionType: NONE
3D reconstructionResolution method: DIFFRACTION PATTERN/LAYERLINES / Symmetry type: 3D CRYSTAL
RefinementResolution: 0.95→15.147 Å / SU ML: 0.16 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 34.66 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.3073 356 10.07 %
Rwork0.2491 3181 -
obs0.2558 3537 77.57 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 31.27 Å2 / Biso mean: 6.7458 Å2 / Biso min: 0.56 Å2
Refinement stepCycle: final / Resolution: 0.95→15.147 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms83 0 0 4 87
Biso mean---8.28 -
Num. residues----10
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON CRYSTALLOGRAPHYf_bond_d0.05984
ELECTRON CRYSTALLOGRAPHYf_angle_d3.442113
ELECTRON CRYSTALLOGRAPHYf_chiral_restr0.17211
ELECTRON CRYSTALLOGRAPHYf_plane_restr0.05215
ELECTRON CRYSTALLOGRAPHYf_dihedral_angle_d34.42430
LS refinement shell

Refine-ID: ELECTRON CRYSTALLOGRAPHY / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
0.9502-1.08760.37781160.2993103677
1.0876-1.37010.27571190.2511105778
1.3701-15.1470.29471210.2252108877

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