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- EMDB-41198: Tropomyosin-receptor kinase fused gene protein (TRK-fused gene pr... -

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Basic information

Entry
Database: EMDB / ID: EMD-41198
TitleTropomyosin-receptor kinase fused gene protein (TRK-fused gene protein; TFG) Low Complexity Domain (residues 237-327) P285L mutant, amyloid fiber
Map data
Sample
  • Complex: amyloid fibril of protein TFG P285L
    • Protein or peptide: TRK-fused gene protein Low Complexity Domain P285L mutant
  • Ligand: water
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 / endoplasmic reticulum exit site / endoplasmic reticulum to Golgi vesicle-mediated transport / bioluminescence / generation of precursor metabolites and energy / Signaling by ALK fusions and activated point mutants / positive regulation of canonical NF-kappaB signal transduction / intracellular membrane-bounded organelle / identical protein binding ...COPII vesicle coating / COPII-mediated vesicle transport / endoplasmic reticulum exit site / endoplasmic reticulum to Golgi vesicle-mediated transport / bioluminescence / generation of precursor metabolites and energy / Signaling by ALK fusions and activated point mutants / 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 / : / PB1 domain profile. / 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: 2.59 Å
AuthorsRosenberg GM / Sawaya MR / Boyer DR / Ge P / Abskharon R / Eisenberg DS
Funding support United States, 6 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 Director1S10OD018111 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)1U24GM116792 United States
National Science Foundation (NSF, United States)DBI-1338135 United States
National Science Foundation (NSF, United States)DMR-1548924 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_41198.png

Downloads & links

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Map

FileDownload / File: emd_41198.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesX (Sec.)Y (Row.)Z (Col.)
0.54 Å/pix.
x 384 pix.
= 206.976 Å		0.54 Å/pix.
x 384 pix.
= 206.976 Å		0.54 Å/pix.
x 384 pix.
= 206.976 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.539 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 3.0
Minimum - Maximum-14.732647999999999 - 19.962502000000001
Average (Standard dev.)-0.000000000000837 (±1.0)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 206.97598 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_41198_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_41198_half_map_2.map
Projections & Slices
AxesZYX

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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 P285L

EntireName: amyloid fibril of protein TFG P285L
Components
  • Complex: amyloid fibril of protein TFG P285L
    • Protein or peptide: TRK-fused gene protein Low Complexity Domain P285L mutant
  • Ligand: water

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Supramolecule #1: amyloid fibril of protein TFG P285L

SupramoleculeName: amyloid fibril of protein TFG P285L / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: TRK-fused gene protein Low Complexity Domain P285L mutant

MacromoleculeName: TRK-fused gene protein Low Complexity Domain P285L mutant
type: protein_or_peptide / ID: 1 / Number of copies: 20 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 40.464754 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 QYGIQYSASY SQQTGPQQLQ QFQ GYGQQP TSQAPAPAFS GQPQQLPAQP PQQYQASNYP AQ

UniProtKB: Uncharacterized protein, Protein TFG

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Macromolecule #2: water

MacromoleculeName: water / type: ligand / ID: 2 / Number of copies: 240 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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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
VitrificationCryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV / Details: 8 seconds, blot force 0.

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Number real images: 7920 / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.6 µm / Nominal defocus min: 1.8 µm / Nominal magnification: 81000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionNumber classes used: 1
Applied symmetry - Helical parameters - Δz: 2.39 Å
Applied symmetry - Helical parameters - Δ&Phi: 179.02 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 2.59 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 193640
Startup modelType of model: NONE
Final angle assignmentType: NOT APPLICABLE

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: FLEXIBLE FIT / Overall B value: 14.16 / Target criteria: Correlation coefficient
Output model

PDB-8ter:
Tropomyosin-receptor kinase fused gene protein (TRK-fused gene protein; TFG) Low Complexity Domain (residues 237-327) P285L mutant, amyloid fiber

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