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- PDB-6hrf: Straight filament from sporadic Alzheimer's disease brain -

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Entry
Database: PDB / ID: 6hrf
TitleStraight filament from sporadic Alzheimer's disease brain
ComponentsMicrotubule-associated protein tau
KeywordsPROTEIN FIBRIL / Tau / helical / filament / fibril / amyloid / Alzheimer's disease / SF / straight filament / NFT / neurofibrillary tangly
Function / homology
Function and homology information


plus-end-directed organelle transport along microtubule / histone-dependent DNA binding / negative regulation of establishment of protein localization to mitochondrion / neurofibrillary tangle / microtubule lateral binding / axonal transport / positive regulation of protein localization to synapse / main axon / phosphatidylinositol bisphosphate binding / regulation of long-term synaptic depression ...plus-end-directed organelle transport along microtubule / histone-dependent DNA binding / negative regulation of establishment of protein localization to mitochondrion / neurofibrillary tangle / microtubule lateral binding / axonal transport / positive regulation of protein localization to synapse / main axon / phosphatidylinositol bisphosphate binding / regulation of long-term synaptic depression / tubulin complex / negative regulation of tubulin deacetylation / generation of neurons / regulation of chromosome organization / rRNA metabolic process / axonal transport of mitochondrion / regulation of mitochondrial fission / axon development / central nervous system neuron development / intracellular distribution of mitochondria / regulation of microtubule polymerization / microtubule polymerization / lipoprotein particle binding / minor groove of adenine-thymine-rich DNA binding / dynactin binding / negative regulation of mitochondrial membrane potential / apolipoprotein binding / glial cell projection / axolemma / protein polymerization / negative regulation of mitochondrial fission / Caspase-mediated cleavage of cytoskeletal proteins / regulation of microtubule polymerization or depolymerization / positive regulation of axon extension / neurofibrillary tangle assembly / Activation of AMPK downstream of NMDARs / synapse assembly / regulation of cellular response to heat / supramolecular fiber organization / positive regulation of protein localization / regulation of calcium-mediated signaling / somatodendritic compartment / cellular response to brain-derived neurotrophic factor stimulus / cytoplasmic microtubule organization / axon cytoplasm / positive regulation of microtubule polymerization / stress granule assembly / phosphatidylinositol binding / regulation of microtubule cytoskeleton organization / nuclear periphery / protein phosphatase 2A binding / positive regulation of superoxide anion generation / cellular response to reactive oxygen species / astrocyte activation / Hsp90 protein binding / microglial cell activation / cellular response to nerve growth factor stimulus / response to lead ion / synapse organization / PKR-mediated signaling / protein homooligomerization / regulation of synaptic plasticity / SH3 domain binding / memory / microtubule cytoskeleton organization / cytoplasmic ribonucleoprotein granule / neuron projection development / cell-cell signaling / single-stranded DNA binding / protein-folding chaperone binding / actin binding / cellular response to heat / microtubule cytoskeleton / cell body / growth cone / double-stranded DNA binding / microtubule binding / protein-macromolecule adaptor activity / dendritic spine / sequence-specific DNA binding / microtubule / amyloid fibril formation / learning or memory / neuron projection / regulation of autophagy / membrane raft / axon / negative regulation of gene expression / neuronal cell body / dendrite / DNA damage response / protein kinase binding / enzyme binding / mitochondrion / DNA binding / RNA binding / extracellular region / identical protein binding / nucleus / plasma membrane
Similarity search - Function
Microtubule-associated protein Tau / Microtubule associated protein, tubulin-binding repeat / 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: 3.3 Å
AuthorsFalcon, B. / Zhang, W. / Schweighauser, M. / Murzin, A.G. / Vidal, R. / Garringer, H.J. / Ghetti, B. / Scheres, S.H.W. / Goedert, M.
Funding support United Kingdom, United States, 5items
OrganizationGrant numberCountry
Medical Research Council (United Kingdom)MC_U105184291 United Kingdom
Medical Research Council (United Kingdom)MC_UP_A025_1013 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: Acta Neuropathol / Year: 2018
Title: Tau filaments from multiple cases of sporadic and inherited Alzheimer's disease adopt a common fold.
Authors: Benjamin Falcon / Wenjuan Zhang / Manuel Schweighauser / Alexey G Murzin / Ruben Vidal / Holly J Garringer / Bernardino Ghetti / Sjors H W Scheres / Michel Goedert /
Abstract: The ordered assembly of tau protein into abnormal filaments is a defining characteristic of Alzheimer's disease (AD) and other neurodegenerative disorders. It is not known if the structures of tau ...The ordered assembly of tau protein into abnormal filaments is a defining characteristic of Alzheimer's disease (AD) and other neurodegenerative disorders. It is not known if the structures of tau filaments vary within, or between, the brains of individuals with AD. We used a combination of electron cryo-microscopy (cryo-EM) and immuno-gold negative-stain electron microscopy (immuno-EM) to determine the structures of paired helical filaments (PHFs) and straight filaments (SFs) from the frontal cortex of 17 cases of AD (15 sporadic and 2 inherited) and 2 cases of atypical AD (posterior cortical atrophy). The high-resolution structures of PHFs and SFs from the frontal cortex of 3 cases of AD, 2 sporadic and 1 inherited, were determined by cryo-EM. We also used immuno-EM to study the PHFs and SFs from a number of cortical and subcortical brain regions. PHFs outnumbered SFs in all AD cases. By cryo-EM, PHFs and SFs were made of two C-shaped protofilaments with a combined cross-β/β-helix structure, as described previously for one case of AD. The higher resolution structures obtained here showed two additional amino acids at each end of the protofilament. The immuno-EM findings, which indicated the presence of repeats 3 and 4, but not of the N-terminal regions of repeats 1 and 2, of tau in the filament cores of all AD cases, were consistent with the cryo-EM results. These findings show that there is no significant variation in tau filament structures between individuals with AD. This knowledge will be crucial for understanding the mechanisms that underlie tau filament formation and for developing novel diagnostics and therapies.
History
DepositionSep 26, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 10, 2018Provider: repository / Type: Initial release
Revision 1.1Nov 7, 2018Group: Data collection / Database references / Structure summary
Category: citation / entity
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _entity.formula_weight
Revision 1.2Dec 18, 2019Group: Other / Category: atom_sites
Item: _atom_sites.fract_transf_matrix[1][1] / _atom_sites.fract_transf_matrix[2][2] / _atom_sites.fract_transf_matrix[3][3]
Revision 1.3Mar 30, 2022Group: Author supporting evidence / Database references / Category: citation / database_2 / pdbx_audit_support
Item: _citation.country / _database_2.pdbx_DOI ..._citation.country / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_audit_support.funding_organization
Revision 1.4Jul 10, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond / em_admin / Item: _em_admin.last_update

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Assembly

Deposited unit
A: Microtubule-associated protein tau
B: Microtubule-associated protein tau
C: Microtubule-associated protein tau
D: Microtubule-associated protein tau
E: Microtubule-associated protein tau
F: Microtubule-associated protein tau


Theoretical massNumber of molelcules
Total (without water)275,5196
Polymers275,5196
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: microscopy
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area26040 Å2
ΔGint-88 kcal/mol
Surface area26300 Å2
MethodPISA

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Components

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


Mass: 45919.871 Da / Num. of mol.: 6 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Tissue: Brain / 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 sporadic Alzheimer'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.FormulaBuffer-ID
120 mMTris-HCl1
2100 mMNaCl1
SpecimenConc.: 0.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: Dispersed filaments
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 FIELD / Nominal defocus max: 2800 nm / Nominal defocus min: 1700 nm / Cs: 2.7 mm
Image recordingElectron dose: 1.2 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
13REFMAC5.7.0032model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: -1.04 ° / Axial rise/subunit: 4.76 Å / Axial symmetry: C1
3D reconstructionResolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 27103 / Symmetry type: HELICAL
Atomic model buildingB value: 82 / 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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