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- PDB-6gx5: Narrow Pick Filament from Pick's disease brain -

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Basic information

Entry
Database: PDB / ID: 6gx5
TitleNarrow Pick Filament from Pick's disease brain
ComponentsMicrotubule-associated protein tauTau protein
KeywordsPROTEIN FIBRIL / tau protein / tau / Pick's disease / tauopathy / neurodegenerative disease / proteinopathy / amyloid / filament / helical / Pick body / fibril / neurodegeneration / MAPT / microtubule-associated protein tau
Function / homology
Function and homology information


plus-end-directed organelle transport along microtubule / axonal transport / histone-dependent DNA binding / neurofibrillary tangle assembly / positive regulation of diacylglycerol kinase activity / negative regulation of establishment of protein localization to mitochondrion / neurofibrillary tangle / positive regulation of protein localization to synapse / microtubule lateral binding / tubulin complex ...plus-end-directed organelle transport along microtubule / axonal transport / histone-dependent DNA binding / neurofibrillary tangle assembly / positive regulation of diacylglycerol kinase activity / negative regulation of establishment of protein localization to mitochondrion / neurofibrillary tangle / positive regulation of protein localization to synapse / microtubule lateral binding / tubulin complex / phosphatidylinositol bisphosphate binding / main axon / regulation of long-term synaptic depression / negative regulation of kinase activity / negative regulation of tubulin deacetylation / generation of neurons / regulation of chromosome organization / positive regulation of protein localization / rRNA metabolic process / internal protein amino acid acetylation / regulation of mitochondrial fission / lipoprotein particle binding / intracellular distribution of mitochondria / axonal transport of mitochondrion / axon development / central nervous system neuron development / regulation of microtubule polymerization / microtubule polymerization / minor groove of adenine-thymine-rich DNA binding / negative regulation of mitochondrial membrane potential / dynactin binding / glial cell projection / apolipoprotein binding / protein polymerization / negative regulation of mitochondrial fission / axolemma / Caspase-mediated cleavage of cytoskeletal proteins / regulation of microtubule polymerization or depolymerization / positive regulation of axon extension / supramolecular fiber organization / Activation of AMPK downstream of NMDARs / regulation of microtubule cytoskeleton organization / stress granule assembly / cytoplasmic microtubule organization / regulation of cellular response to heat / regulation of calcium-mediated signaling / axon cytoplasm / positive regulation of microtubule polymerization / cellular response to brain-derived neurotrophic factor stimulus / somatodendritic compartment / synapse assembly / phosphatidylinositol binding / nuclear periphery / cellular response to nerve growth factor stimulus / positive regulation of superoxide anion generation / protein phosphatase 2A binding / regulation of autophagy / astrocyte activation / synapse organization / microglial cell activation / response to lead ion / Hsp90 protein binding / regulation of synaptic plasticity / PKR-mediated signaling / protein homooligomerization / cytoplasmic ribonucleoprotein granule / memory / microtubule cytoskeleton organization / SH3 domain binding / cellular response to reactive oxygen species / neuron projection development / activation of cysteine-type endopeptidase activity involved in apoptotic process / microtubule cytoskeleton / protein-macromolecule adaptor activity / single-stranded DNA binding / cell-cell signaling / cellular response to heat / cell body / actin binding / growth cone / protein-folding chaperone binding / double-stranded DNA binding / microtubule binding / microtubule / amyloid fibril formation / sequence-specific DNA binding / dendritic spine / learning or memory / neuron projection / nuclear speck / membrane raft / axon / negative regulation of gene expression / dendrite / neuronal cell body / DNA damage response / protein kinase binding / enzyme binding / mitochondrion / DNA binding
Similarity search - Function
: / Microtubule associated protein, tubulin-binding repeat / Microtubule-associated protein Tau / Tau and MAP protein, tubulin-binding repeat / Tau and MAP proteins tubulin-binding repeat signature. / Tau and MAP proteins tubulin-binding repeat profile.
Similarity search - Domain/homology
Microtubule-associated protein tau
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsFalcon, B. / Zhang, W. / Murzin, A.G. / Murshudov, G. / Garringer, H.J. / Vidal, R. / Crowther, R.A. / Ghetti, B. / Scheres, S.H.W. / Goedert, M.
Funding support United Kingdom, United States, 6items
OrganizationGrant numberCountry
Medical Research Council (United Kingdom)MC_U105184291 United Kingdom
Medical Research Council (United Kingdom)MC_UP_A025_1013 United Kingdom
Medical Research Council (United Kingdom)MC_UP_A025_1012 United Kingdom
National Institutes of Health/National Institute on Aging (NIH/NIA)P30-AG010133 United States
European UnionJoint Programme-Neurodegeneration Research United Kingdom
European UnionHorizon 2020 IMPRiND United Kingdom
CitationJournal: Nature / Year: 2018
Title: Structures of filaments from Pick's disease reveal a novel tau protein fold.
Authors: Benjamin Falcon / Wenjuan Zhang / Alexey G Murzin / Garib Murshudov / Holly J Garringer / Ruben Vidal / R Anthony Crowther / Bernardino Ghetti / Sjors H W Scheres / Michel Goedert /
Abstract: The ordered assembly of tau protein into abnormal filamentous inclusions underlies many human neurodegenerative diseases. Tau assemblies seem to spread through specific neural networks in each ...The ordered assembly of tau protein into abnormal filamentous inclusions underlies many human neurodegenerative diseases. Tau assemblies seem to spread through specific neural networks in each disease, with short filaments having the greatest seeding activity. The abundance of tau inclusions strongly correlates with disease symptoms. Six tau isoforms are expressed in the normal adult human brain-three isoforms with four microtubule-binding repeats each (4R tau) and three isoforms that lack the second repeat (3R tau). In various diseases, tau filaments can be composed of either 3R or 4R tau, or of both. Tau filaments have distinct cellular and neuroanatomical distributions, with morphological and biochemical differences suggesting that they may be able to adopt disease-specific molecular conformations. Such conformers may give rise to different neuropathological phenotypes, reminiscent of prion strains. However, the underlying structures are not known. Using electron cryo-microscopy, we recently reported the structures of tau filaments from patients with Alzheimer's disease, which contain both 3R and 4R tau. Here we determine the structures of tau filaments from patients with Pick's disease, a neurodegenerative disorder characterized by frontotemporal dementia. The filaments consist of residues Lys254-Phe378 of 3R tau, which are folded differently from the tau filaments in Alzheimer's disease, establishing the existence of conformers of assembled tau. The observed tau fold in the filaments of patients with Pick's disease explains the selective incorporation of 3R tau in Pick bodies, and the differences in phosphorylation relative to the tau filaments of Alzheimer's disease. Our findings show how tau can adopt distinct folds in the human brain in different diseases, an essential step for understanding the formation and propagation of molecular conformers.
History
DepositionJun 26, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 12, 2018Provider: repository / Type: Initial release
Revision 1.1Sep 19, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Dec 18, 2019Group: Other / Category: atom_sites / cell
Item: _atom_sites.fract_transf_matrix[1][1] / _atom_sites.fract_transf_matrix[2][2] ..._atom_sites.fract_transf_matrix[1][1] / _atom_sites.fract_transf_matrix[2][2] / _atom_sites.fract_transf_matrix[3][3] / _cell.Z_PDB
Revision 1.3Mar 30, 2022Group: Author supporting evidence / Database references / Category: database_2 / pdbx_audit_support
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_audit_support.funding_organization

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Structure visualization

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Assembly

Deposited unit
A: Microtubule-associated protein tau
B: Microtubule-associated protein tau
C: Microtubule-associated protein tau


Theoretical massNumber of molelcules
Total (without water)30,4073
Polymers30,4073
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: microscopy
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area15880 Å2
ΔGint-40 kcal/mol
Surface area15780 Å2
MethodPISA

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Components

#1: Protein Microtubule-associated protein tau / Tau protein / Neurofibrillary tangle protein / Paired helical filament-tau / PHF-tau


Mass: 10135.665 Da / Num. of mol.: 3 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Organ: Brain / Tissue: Frontotemporal cortex / References: UniProt: P10636

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Experimental details

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Experiment

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

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Sample preparation

ComponentName: Tau filaments extracted from the frontotemporal cortex of a patient with Pick's disease
Type: TISSUE / Entity ID: all / Source: NATURAL
Source (natural)Organism: Homo sapiens (human) / Organ: Brain / Tissue: Frontotemporal cortex
Buffer solutionpH: 7.4
Buffer component
IDConc.NameFormulaBuffer-ID
150 mMTris-HClTris1
2150 mMNaClSodium chloride1
30.02 %AmphipolA8-351
SpecimenConc.: 0.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: Dispersed filaments
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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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 FIELDBright-field microscopy / Nominal defocus max: 2800 nm / Nominal defocus min: 1700 nm / Cs: 2.7 mm
Image recordingElectron dose: 1.06 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 QUANTUM (4k x 4k)
EM imaging opticsEnergyfilter name: GIF Quantum LS

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Processing

EM software
IDNameVersionCategory
2EPUimage acquisition
4Gctf1.06CTF correction
7Coot0.8.9.1model fitting
12RELION2.13D reconstruction
19REFMAC5.7.0032model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: -0.75 ° / Axial rise/subunit: 4.78 Å / Axial symmetry: C1
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 16097 / Symmetry type: HELICAL
Atomic model buildingB value: 57 / Protocol: AB INITIO MODEL / Space: RECIPROCAL / Target criteria: Fourier shell correlation
Details: Fourier-space refinement of the complete atomic model against the narrow Pick filament map was performed in REFMAC. A stack of three consecutive monomers was refined to preserve nearest- ...Details: Fourier-space refinement of the complete atomic model against the narrow Pick filament map was performed in REFMAC. A stack of three consecutive monomers was refined to preserve nearest-neighbour interactions for the middle chain.

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