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- PDB-8ter: Tropomyosin-receptor kinase fused gene protein (TRK-fused gene pr... -

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Basic information

Entry
Database: PDB / ID: 8ter
TitleTropomyosin-receptor kinase fused gene protein (TRK-fused gene protein; TFG) Low Complexity Domain (residues 237-327) P285L mutant, amyloid fiber
ComponentsTRK-fused gene protein Low Complexity Domain P285L mutant
KeywordsPROTEIN FIBRIL / amyloid / mutation / Charcot-Marie-Tooth disease / Hereditary motor and sensory neuropathy with proximal dominant involvement
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 speciesPurpureocillium lilacinum (fungus)
Homo sapiens (human)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 2.59 Å
AuthorsRosenberg, G.M. / Sawaya, M.R. / Boyer, D.R. / Ge, P. / Abskharon, R. / Eisenberg, D.S.
Funding support United States, 6items
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, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 20, 2023Provider: repository / Type: Initial release
Revision 1.1Dec 27, 2023Group: Database references / Category: citation / citation_author
Item: _citation.page_first / _citation.page_last ..._citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: TRK-fused gene protein Low Complexity Domain P285L mutant
B: TRK-fused gene protein Low Complexity Domain P285L mutant
C: TRK-fused gene protein Low Complexity Domain P285L mutant
D: TRK-fused gene protein Low Complexity Domain P285L mutant
E: TRK-fused gene protein Low Complexity Domain P285L mutant
F: TRK-fused gene protein Low Complexity Domain P285L mutant
G: TRK-fused gene protein Low Complexity Domain P285L mutant
H: TRK-fused gene protein Low Complexity Domain P285L mutant
I: TRK-fused gene protein Low Complexity Domain P285L mutant
J: TRK-fused gene protein Low Complexity Domain P285L mutant
K: TRK-fused gene protein Low Complexity Domain P285L mutant
L: TRK-fused gene protein Low Complexity Domain P285L mutant
M: TRK-fused gene protein Low Complexity Domain P285L mutant
N: TRK-fused gene protein Low Complexity Domain P285L mutant
O: TRK-fused gene protein Low Complexity Domain P285L mutant
P: TRK-fused gene protein Low Complexity Domain P285L mutant
Q: TRK-fused gene protein Low Complexity Domain P285L mutant
R: TRK-fused gene protein Low Complexity Domain P285L mutant
S: TRK-fused gene protein Low Complexity Domain P285L mutant
T: TRK-fused gene protein Low Complexity Domain P285L mutant


Theoretical massNumber of molelcules
Total (without water)809,29520
Polymers809,29520
Non-polymers00
Water4,324240
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
d_1ens_1chain "H"
d_2ens_1chain "B"
d_3ens_1chain "C"
d_4ens_1chain "D"
d_5ens_1chain "E"
d_6ens_1chain "F"
d_7ens_1chain "G"
d_8ens_1chain "A"
d_9ens_1chain "I"
d_10ens_1chain "J"
d_11ens_1chain "K"
d_12ens_1chain "L"
d_13ens_1chain "M"
d_14ens_1chain "N"
d_15ens_1chain "O"
d_16ens_1chain "P"
d_17ens_1chain "Q"
d_18ens_1chain "R"
d_19ens_1chain "S"
d_20ens_1chain "T"

NCS domain segments:

Component-ID: 1 / Ens-ID: ens_1 / Beg auth comp-ID: PRO / Beg label comp-ID: PRO / End auth comp-ID: ALA / End label comp-ID: ALA / Auth seq-ID: 265 - 299 / Label seq-ID: 296 - 330

Dom-IDAuth asym-IDLabel asym-ID
d_1HH
d_2BB
d_3CC
d_4DD
d_5EE
d_6FF
d_7GG
d_8AA
d_9II
d_10JJ
d_11KK
d_12LL
d_13MM
d_14NN
d_15OO
d_16PP
d_17QQ
d_18RR
d_19SS
d_20TT

NCS oper:
IDCodeMatrixVector
1given(-0.998712980305, 0.0507186649144, 6.45984733537E-8), (-0.0507186649144, -0.998712980305, -2.09838129673E-7), (5.38726240611E-8, -2.12844412191E-7, 1)201.594062254, 212.09164224, -7.16598618148
2given(-0.996426333179, 0.0844663397338, 2.24677707307E-7), (-0.0844663397338, -0.996426333179, 1.42244164385E-7), (2.35889627953E-7, 1.22758127578E-7, 1)197.86488024, 215.34746293, -11.942036427
3given(0.999427982571, -0.033818747068, 8.32690516109E-8), (0.033818747068, 0.999427982571, 1.53462292158E-7), (-8.84113227051E-8, -1.50558454058E-7, 1)3.55900969627, -3.4406696878, -4.77697673876
4given(0.994855176374, -0.10130734446, -1.08837231771E-7), (0.10130734446, 0.994855176374, 7.18058336619E-7), (3.55327001592E-8, -7.25390064053E-7, 1)11.0164845764, -9.9517896673, -14.3309371217
5given(-0.99985699065, 0.0169114827604, -6.65741756303E-8), (-0.0169114827604, -0.99985699065, -8.80885530659E-8), (-6.80543629473E-8, -8.69500875556E-8, 1)205.211099747, 208.711372793, -2.38898475459
6given(-0.992999474533, 0.118118768942, 1.36640397159E-7), (-0.118118768942, -0.992999474533, -4.0156753964E-7), (8.82511791494E-8, -4.14896151352E-7, 1)194.027654938, 218.475456353, -16.7189712768
7given(0.997712326339, -0.0676026173382, -1.38371326001E-7), (0.0676026173383, 0.997712326339, 3.10248744566E-7), (1.17081150405E-7, -3.18893260487E-7, 1)7.23278922784, -6.75938025536, -9.55398317304
8given(0.990859775071, -0.134895908557, -6.62964538895E-8), (0.134895908557, 0.990859775071, 1.92637844183E-7), (3.97044323755E-8, -1.99820211339E-7, 1)14.9060027953, -13.0142717603, -19.1079858682
9given(-0.999856991938, -0.0169114065616, 1.6845547956E-7), (0.0169114065614, -0.999856991938, -9.30408983291E-7), (1.84165913654E-7, -9.27427108204E-7, 1)208.71137517, 205.211196685, 2.38806560245
10given(-0.988437193444, 0.15163084982, -8.287389958E-8), (-0.15163084982, -0.988437193444, -2.50626637896E-7), (-1.19918374802E-7, -2.35162450743E-7, 1)190.087411505, 221.471386418, -21.4959656048
11given(0.999427939895, 0.0338200082506, -3.85004157311E-7), (-0.0338200082503, 0.999427939894, 7.79781840719E-7), (4.11156140078E-7, -7.6631491486E-7, 1)-3.44076109347, 3.55906426165, 4.77702659919
12given(0.985730846632, -0.168329135916, -1.8590342928E-7), (0.168329135916, 0.985730846632, 3.72121912065E-7), (1.20611784823E-7, -3.98105011045E-7, 1)18.8967471555, -15.9434351991, -23.8849762695
13given(-0.998713039036, -0.0507175084165, 1.97685583052E-7), (0.0507175084164, -0.998713039036, -3.76869478109E-7), (2.16545050352E-7, -3.6635834158E-7, 1)212.09148135, 201.594230745, 7.16501058664
14given(-0.982742907846, 0.184976693339, 2.37262698523E-7), (-0.184976693339, -0.982742907846, -2.65946759695E-7), (1.83974282057E-7, -3.0524536138E-7, 1)186.047251316, 224.333005468, -26.2729915579
15given(0.997712414683, 0.0676013134997, -3.02632511296E-7), (-0.0676013134993, 0.997712414683, 1.16252189192E-6), (3.80528220472E-7, -1.13940416864E-6, 0.999999999999)-6.75917850109, 7.2324863229, 9.55406415232
16given(0.979474249044, -0.201569331644, -1.75534107111E-7), (0.201569331644, 0.979474249044, 1.16890514602E-7), (1.4836959484E-7, -1.49873541662E-7, 1)22.9841809015, -18.7358958598, -28.6620020418
17given(-0.996426532797, -0.0844639848621, 2.95446630067E-7), (0.0844639848622, -0.996426532797, 3.89883342758E-7), (2.61459760463E-7, 4.13444707109E-7, 1)215.347227958, 197.865144265, 11.9419341321
18given(-0.975924677306, 0.218107827062, 2.51121412115E-7), (-0.218107827062, -0.975924677306, 3.39616921558E-9), (2.45816314171E-7, -5.14571401793E-8, 1)181.912969703, 227.056067531, -31.0500214742
19given(0.972096526729, -0.234581207095, 5.97814521769E-8), (0.234581207095, 0.972096526729, 4.93280914204E-7), (-1.73827774315E-7, -4.65493058186E-7, 1)27.1639843523, -21.3887506425, -33.43893869

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Components

#1: Protein
TRK-fused gene protein Low Complexity Domain P285L mutant / TRK-fused gene protein / TFG


Mass: 40464.754 Da / Num. of mol.: 20 / Mutation: P285L
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Purpureocillium lilacinum (fungus), (gene. exp.) Homo sapiens (human)
Gene: PCL_01928, TFG / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: A0A2U3DNX3, UniProt: Q92734
#2: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 240 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: FILAMENT / 3D reconstruction method: helical reconstruction

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Sample preparation

ComponentName: amyloid fibril of protein TFG P285L / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli BL21(DE3) (bacteria)
Buffer solutionpH: 7.4 / Details: PBS
SpecimenConc.: 10 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Details: 8 seconds, blot force 0

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 81000 X / Nominal defocus max: 2600 nm / Nominal defocus min: 1800 nm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Num. of real images: 7920

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Processing

EM software
IDNameCategory
1EMAN2particle selection
2crYOLOparticle selection
5CTFFINDCTF correction
8Cootmodel fitting
12RELIONclassification
13RELION3D reconstruction
14PHENIXmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: 179.02 ° / Axial rise/subunit: 2.39 Å / Axial symmetry: C1
3D reconstructionResolution: 2.59 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 193640 / Num. of class averages: 1 / Symmetry type: HELICAL
Atomic model buildingB value: 14.16 / Protocol: FLEXIBLE FIT / Space: REAL / Target criteria: Correlation coefficient
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 14.82 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00685680
ELECTRON MICROSCOPYf_angle_d0.8977680
ELECTRON MICROSCOPYf_chiral_restr0.0474700
ELECTRON MICROSCOPYf_plane_restr0.00751080
ELECTRON MICROSCOPYf_dihedral_angle_d18.48921873
Refine LS restraints NCS
Ens-IDDom-IDAsym-IDAuth asym-IDRefine-IDTypeRms dev position (Å)
ens_1d_2HHELECTRON MICROSCOPYNCS constraints4.3454043718E-14
ens_1d_3HHELECTRON MICROSCOPYNCS constraints3.19232789919E-13
ens_1d_4HHELECTRON MICROSCOPYNCS constraints8.6765360443E-14
ens_1d_5HHELECTRON MICROSCOPYNCS constraints4.8481699065E-14
ens_1d_6HHELECTRON MICROSCOPYNCS constraints2.51003575339E-13
ens_1d_7HHELECTRON MICROSCOPYNCS constraints4.50664110757E-11
ens_1d_8HHELECTRON MICROSCOPYNCS constraints9.9387996566E-14
ens_1d_9HHELECTRON MICROSCOPYNCS constraints5.7677383322E-14
ens_1d_10HHELECTRON MICROSCOPYNCS constraints5.5552607591E-14
ens_1d_11HHELECTRON MICROSCOPYNCS constraints7.56087694412E-11
ens_1d_12HHELECTRON MICROSCOPYNCS constraints5.5329054943E-14
ens_1d_13HHELECTRON MICROSCOPYNCS constraints4.2478377151E-14
ens_1d_14HHELECTRON MICROSCOPYNCS constraints4.8930751866E-14
ens_1d_15HHELECTRON MICROSCOPYNCS constraints5.0079448344E-14
ens_1d_16HHELECTRON MICROSCOPYNCS constraints5.477283682E-14
ens_1d_17HHELECTRON MICROSCOPYNCS constraints5.7847774781E-14
ens_1d_18HHELECTRON MICROSCOPYNCS constraints8.0619664905E-14
ens_1d_19HHELECTRON MICROSCOPYNCS constraints4.9794758553E-14
ens_1d_20HHELECTRON MICROSCOPYNCS constraints4.5702781054E-14

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