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- EMDB-41195: Tropomyosin-receptor kinase fused gene protein (TRK-fused gene pr... -

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Basic information

Entry
Database: EMDB / ID: EMD-41195
TitleTropomyosin-receptor kinase fused gene protein (TRK-fused gene protein; TFG) Low Complexity Domain (residues 237-327) G269V mutant, amyloid fiber
Map data
Sample
  • Complex: amyloid fibril of protein TFG G269V
    • Protein or peptide: TRK-fused gene protein Low Complexity Domain G269V mutant
Keywordsamyloid / mutation / Charcot-Marie-Tooth disease / Hereditary motor and sensory neuropathy with proximal dominant involvement / PROTEIN FIBRIL
Function / homology
Function and homology information


COPII vesicle coating / COPII-mediated vesicle transport / Signaling by ALK fusions and activated point mutants / endoplasmic reticulum to Golgi vesicle-mediated transport / endoplasmic reticulum exit site / bioluminescence / generation of precursor metabolites and energy / positive regulation of canonical NF-kappaB signal transduction / intracellular membrane-bounded organelle / identical protein binding ...COPII vesicle coating / COPII-mediated vesicle transport / Signaling by ALK fusions and activated point mutants / endoplasmic reticulum to Golgi vesicle-mediated transport / endoplasmic reticulum exit site / bioluminescence / generation of precursor metabolites and energy / positive regulation of canonical NF-kappaB signal transduction / intracellular membrane-bounded organelle / identical protein binding / cytosol / cytoplasm
Similarity search - Function
Protein TFG / TFG, PB1 domain / PB1 domain / PB1 domain / PB1 domain profile. / PB1 domain / Green fluorescent protein, GFP / Green fluorescent protein-related / Green fluorescent protein / Green fluorescent protein
Similarity search - Domain/homology
Uncharacterized protein / Protein TFG
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodhelical reconstruction / cryo EM / Resolution: 2.84 Å
AuthorsRosenberg GM / Sawaya MR / Boyer DR / Ge P / Abskharon R / Eisenberg DS
Funding support United States, 3 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute on Aging (NIH/NIA)R01AG048120 United States
National Institutes of Health/National Institute on Aging (NIH/NIA)R01AG07895 United States
National Institutes of Health/Office of the DirectorU24 GM129541 United States
CitationJournal: PNAS Nexus / Year: 2023
Title: Fibril structures of TFG protein mutants validate the identification of TFG as a disease-related amyloid protein by the IMPAcT method.
Authors: Gregory M Rosenberg / Romany Abskharon / David R Boyer / Peng Ge / Michael R Sawaya / David S Eisenberg /
Abstract: We previously presented a bioinformatic method for identifying diseases that arise from a mutation in a protein's low-complexity domain that drives the protein into pathogenic amyloid fibrils. One ...We previously presented a bioinformatic method for identifying diseases that arise from a mutation in a protein's low-complexity domain that drives the protein into pathogenic amyloid fibrils. One protein so identified was the tropomyosin-receptor kinase-fused gene protein (TRK-fused gene protein or TFG). Mutations in TFG are associated with degenerative neurological conditions. Here, we present experimental evidence that confirms our prediction that these conditions are amyloid-related. We find that the low-complexity domain of TFG containing the disease-related mutations G269V or P285L forms amyloid fibrils, and we determine their structures using cryo-electron microscopy (cryo-EM). These structures are unmistakably amyloid in nature and confirm the propensity of the mutant TFG low-complexity domain to form amyloid fibrils. Also, despite resulting from a pathogenic mutation, the fibril structures bear some similarities to other amyloid structures that are thought to be nonpathogenic and even functional, but there are other factors that support these structures' relevance to disease, including an increased propensity to form amyloid compared with the wild-type sequence, structure-stabilizing influence from the mutant residues themselves, and double-protofilament amyloid cores. Our findings elucidate two potentially disease-relevant structures of a previously unknown amyloid and also show how the structural features of pathogenic amyloid fibrils may not conform to the features commonly associated with pathogenicity.
History
DepositionJul 6, 2023-
Header (metadata) releaseDec 20, 2023-
Map releaseDec 20, 2023-
UpdateDec 27, 2023-
Current statusDec 27, 2023Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_41195.png

Downloads & links

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Map

FileDownload / File: emd_41195.map.gz / Format: CCP4 / Size: 307.5 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.86 Å
Density
Contour LevelBy AUTHOR: 5.0
Minimum - Maximum-19.133392000000001 - 31.496825999999999
Average (Standard dev.)0.000000000001824 (±1.0)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin000
Dimensions432432432
Spacing432432432
CellA=B=C: 371.52002 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_41195_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_41195_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : amyloid fibril of protein TFG G269V

EntireName: amyloid fibril of protein TFG G269V
Components
  • Complex: amyloid fibril of protein TFG G269V
    • Protein or peptide: TRK-fused gene protein Low Complexity Domain G269V mutant

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Supramolecule #1: amyloid fibril of protein TFG G269V

SupramoleculeName: amyloid fibril of protein TFG G269V / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: TRK-fused gene protein Low Complexity Domain G269V mutant

MacromoleculeName: TRK-fused gene protein Low Complexity Domain G269V mutant
type: protein_or_peptide / ID: 1 / Number of copies: 30 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 40.490789 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString: MSYYHHHHHH DYDIPTTENL YFQGAMVSKG EEDNMAIIKE FMRFKVHMEG SVNGHEFEIE GEGEGRPYEG TQTAKLKVTK GGPLPFAWD ILSPQFMYGS KAYVKHPADI PDYLKLSFPE GFKWERVMNF EDGGVVTVTQ DSSLQDGEFI YKVKLRGTNF P SDGPVMQK ...String:
MSYYHHHHHH DYDIPTTENL YFQGAMVSKG EEDNMAIIKE FMRFKVHMEG SVNGHEFEIE GEGEGRPYEG TQTAKLKVTK GGPLPFAWD ILSPQFMYGS KAYVKHPADI PDYLKLSFPE GFKWERVMNF EDGGVVTVTQ DSSLQDGEFI YKVKLRGTNF P SDGPVMQK KTMGWEASSE RMYPEDGALK GEIKQRLKLK DGGHYDAEVK TTYKAKKPVQ LPGAYNVNIK LDITSHNEDY TI VEQYERA EGRHSTGGMD ELYKAGTMDP GQIEGQMYQQ YQQQAGYGAQ QPQAPPQQPQ QYVIQYSASY SQQTGPQQPQ QFQ GYGQQP TSQAPAPAFS GQPQQLPAQP PQQYQASNYP AQ

UniProtKB: Uncharacterized protein, Protein TFG

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Experimental details

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Structure determination

Methodcryo EM
Processinghelical reconstruction
Aggregation statefilament

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Sample preparation

Concentration10 mg/mL
BufferpH: 7.4 / Details: PBS
GridModel: Quantifoil R1.2/1.3 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 240 sec.
VitrificationCryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV / Details: 8 seconds, blot force 0.

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.6 µm / Nominal defocus min: 1.8 µm / Nominal magnification: 105000
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Number real images: 15192 / Average electron dose: 50.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final angle assignmentType: NOT APPLICABLE
Final reconstructionNumber classes used: 1
Applied symmetry - Helical parameters - Δz: 4.93 Å
Applied symmetry - Helical parameters - Δ&Phi: -3.07 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 2.84 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 31643

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: FLEXIBLE FIT / Overall B value: 44.55 / Target criteria: Correlation coefficient
Output model

PDB-8teq:
Tropomyosin-receptor kinase fused gene protein (TRK-fused gene protein; TFG) Low Complexity Domain (residues 237-327) G269V mutant, amyloid fiber

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