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- EMDB-7466: Segment NFGTFS, with familial mutation A315T and phosphorylated t... -
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Open data
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Basic information
Entry | Database: EMDB / ID: EMD-7466 | |||||||||
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Title | Segment NFGTFS, with familial mutation A315T and phosphorylated threonine, from the low complexity domain of TDP-43, residues 312-317 | |||||||||
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Function / homology | ![]() 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 | |||||||||
Biological species | ![]() | |||||||||
Method | electron crystallography / cryo EM | |||||||||
![]() | Guenther EL / Cao Q / Boyer DR / Sawaya MR / Eisenberg DS | |||||||||
Funding support | ![]()
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![]() | ![]() 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 |
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Structure visualization
Movie |
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Structure viewer | EM map: ![]() ![]() ![]() |
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 456.1 KB | ![]() | |
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Header (meta data) | ![]() ![]() | 15.1 KB 15.1 KB | Display Display | ![]() |
Images | ![]() | 262.2 KB | ||
Filedesc structureFactors | ![]() | 106.4 KB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Validation report
Summary document | ![]() | 298.2 KB | Display | ![]() |
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Full document | ![]() | 297.8 KB | Display | |
Data in XML | ![]() | 4 KB | Display | |
Data in CIF | ![]() | 4.4 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 6cf4MC ![]() 7467C ![]() 8857C ![]() 5whnC ![]() 5whpC ![]() 5wiaC ![]() 5wiqC ![]() 5wkbC ![]() 5wkdC ![]() 6cb9C ![]() 6cewC ![]() 6cfhC M: atomic model generated by this map C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
File | ![]() | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Projections & slices | Image control
Images are generated by Spider. generated in cubic-lattice coordinate | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X: 0.197 Å / Y: 0.197 Å / Z: 0.188 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 19 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
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Sample components
-Entire : crystal of NFGTFS phosphorylated on threonine.
Entire | Name: crystal of NFGTFS phosphorylated on threonine. |
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Components |
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-Supramolecule #1: crystal of NFGTFS phosphorylated on threonine.
Supramolecule | Name: crystal of NFGTFS phosphorylated on threonine. / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 |
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Source (natural) | Organism: ![]() |
-Macromolecule #1: NFGTFS
Macromolecule | Name: NFGTFS / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 751.679 Da |
Sequence | String: NFG(TPO)FS |
-Macromolecule #2: water
Macromolecule | Name: water / type: ligand / ID: 2 / Number of copies: 1 / Formula: HOH |
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Molecular weight | Theoretical: 18.015 Da |
Chemical component information | ![]() ChemComp-HOH: |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | electron crystallography |
Aggregation state | 3D array |
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Sample preparation
Buffer | pH: 4 |
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Grid | Model: Quantifoil R2/2 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY ARRAY / Support film - Film thickness: 30.0 nm / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Atmosphere: AIR |
Vitrification | Cryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV |
Crystal formation | Lipid mixture: none / Instrument: microcentrifuge tube / Atmosphere: air, sealed chamber / Temperature: 310.0 K / Time: 4.0 DAY Details: Crystals were prepared by shaking peptide in microcentrifuge tube at 37 deg Celsius for 4 days. |
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Electron microscopy
Microscope | FEI TECNAI F20 |
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Temperature | Min: 100.0 K / Max: 100.0 K |
Image recording | Film or detector model: TVIPS TEMCAM-F416 (4k x 4k) / Digitization - Dimensions - Width: 4096 pixel / Digitization - Dimensions - Height: 4096 pixel / Number grids imaged: 1 / Number diffraction images: 100 / Average exposure time: 3.0 sec. / Average electron dose: 0.01 e/Å2 Details: The detector was operated in rolling shutter mode with 2X2 pixel binning. |
Electron beam | Acceleration voltage: 200 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: DIFFRACTION / Camera length: 819 mm |
Sample stage | Specimen holder model: GATAN 626 SINGLE TILT LIQUID NITROGEN CRYO TRANSFER HOLDER Cooling holder cryogen: NITROGEN |
Experimental equipment | ![]() Model: Tecnai F20 / Image courtesy: FEI Company |
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Image processing
Final reconstruction | Resolution method: DIFFRACTION PATTERN/LAYERLINES / Software - Name: SHELXD (ver. 2013/2) / Software - details: direct methods Details: Density map was obtained using measured diffraction intensities and phases acquired from a crystallographic direct methods program, shelxd. | ||||||||||||||||||||||||||||
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Crystal parameters | Unit cell - A: 23.650 Å / Unit cell - B: 4.720 Å / Unit cell - C: 30.060 Å / Unit cell - γ: 90.00 ° / Unit cell - α: 90.00 ° / Unit cell - β: 90.00 ° / Space group: P 21 21 21 | ||||||||||||||||||||||||||||
Crystallography statistics | Number intensities measured: 15891 / Number structure factors: 4177 / Fourier space coverage: 86.6 / R sym: 17.2 / R merge: 17.2 / Overall phase error: 32.2 / Overall phase residual: 32.2 / Phase error rejection criteria: 0 / High resolution: 0.75 Å Shell:
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-Atomic model buiding 1
Refinement | Space: RECIPROCAL / Protocol: OTHER / Overall B value: 19.6 / Target criteria: maximum likihood |
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Output model | ![]() PDB-6cf4: |