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- PDB-7nrq: Paired helical filament from primary age-related tauopathy brain -

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Basic information

Entry
Database: PDB / ID: 7nrq
TitlePaired helical filament from primary age-related tauopathy brain
ComponentsMicrotubule-associated protein tau
KeywordsPROTEIN FIBRIL / Tau filament
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 / tubulin complex / positive regulation of protein localization to synapse / phosphatidylinositol bisphosphate binding / negative regulation of tubulin deacetylation ...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 / tubulin complex / positive regulation of protein localization to synapse / phosphatidylinositol bisphosphate binding / negative regulation of tubulin deacetylation / generation of neurons / rRNA metabolic process / axonal transport of mitochondrion / regulation of chromosome organization / regulation of mitochondrial fission / axon development / central nervous system neuron development / intracellular distribution of mitochondria / minor groove of adenine-thymine-rich DNA binding / lipoprotein particle binding / microtubule polymerization / negative regulation of mitochondrial membrane potential / regulation of microtubule polymerization / dynactin binding / apolipoprotein binding / main axon / protein polymerization / glial cell projection / axolemma / negative regulation of mitochondrial fission / Caspase-mediated cleavage of cytoskeletal proteins / regulation of microtubule polymerization or depolymerization / neurofibrillary tangle assembly / positive regulation of axon extension / Activation of AMPK downstream of NMDARs / regulation of cellular response to heat / positive regulation of superoxide anion generation / supramolecular fiber organization / synapse assembly / regulation of long-term synaptic depression / positive regulation of protein localization / cellular response to brain-derived neurotrophic factor stimulus / regulation of calcium-mediated signaling / cytoplasmic microtubule organization / positive regulation of microtubule polymerization / somatodendritic compartment / axon cytoplasm / astrocyte activation / stress granule assembly / phosphatidylinositol binding / nuclear periphery / regulation of microtubule cytoskeleton organization / protein phosphatase 2A binding / cellular response to reactive oxygen species / Hsp90 protein binding / microglial cell activation / synapse organization / PKR-mediated signaling / cellular response to nerve growth factor stimulus / protein homooligomerization / regulation of synaptic plasticity / SH3 domain binding / response to lead ion / microtubule cytoskeleton organization / memory / cytoplasmic ribonucleoprotein granule / neuron projection development / cell-cell signaling / single-stranded DNA binding / protein-folding chaperone binding / actin binding / cellular response to heat / growth cone / microtubule cytoskeleton / cell body / double-stranded DNA binding / protein-macromolecule adaptor activity / microtubule binding / dendritic spine / sequence-specific DNA binding / amyloid fibril formation / microtubule / 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: 2.76 Å
AuthorsShi, Y. / Murzin, A.G. / Falcon, B. / Epstein, A. / Machin, J. / Tempest, P. / Newell, K.L. / Vidal, R. / Garringer, H.J. / Sahara, N. ...Shi, Y. / Murzin, A.G. / Falcon, B. / Epstein, A. / Machin, J. / Tempest, P. / Newell, K.L. / Vidal, R. / Garringer, H.J. / Sahara, N. / Higuchi, M. / Ghetti, B. / Jang, M. / Scheres, S.H.W. / Goedert, M.
Funding support United Kingdom, European Union, United States, Japan, 6items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom)MC_UP_A025_1013 United Kingdom
Medical Research Council (MRC, United Kingdom)MC_U105184291 United Kingdom
Innovative Medicines Initiative116060European Union
National Institutes of Health/National Institute on Aging (NIH/NIA)P30-AG010133 United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)U01-NS110437 United States
Japan Agency for Medical Research and Development (AMED)JP20dm0207072 Japan
CitationJournal: Acta Neuropathol / Year: 2021
Title: Cryo-EM structures of tau filaments from Alzheimer's disease with PET ligand APN-1607.
Authors: Yang Shi / Alexey G Murzin / Benjamin Falcon / Alexander Epstein / Jonathan Machin / Paul Tempest / Kathy L Newell / Ruben Vidal / Holly J Garringer / Naruhiko Sahara / Makoto Higuchi / ...Authors: Yang Shi / Alexey G Murzin / Benjamin Falcon / Alexander Epstein / Jonathan Machin / Paul Tempest / Kathy L Newell / Ruben Vidal / Holly J Garringer / Naruhiko Sahara / Makoto Higuchi / Bernardino Ghetti / Ming-Kuei Jang / Sjors H W Scheres / Michel Goedert /
Abstract: Tau and Aβ assemblies of Alzheimer's disease (AD) can be visualized in living subjects using positron emission tomography (PET). Tau assemblies comprise paired helical and straight filaments (PHFs ...Tau and Aβ assemblies of Alzheimer's disease (AD) can be visualized in living subjects using positron emission tomography (PET). Tau assemblies comprise paired helical and straight filaments (PHFs and SFs). APN-1607 (PM-PBB3) is a recently described PET ligand for AD and other tau proteinopathies. Since it is not known where in the tau folds PET ligands bind, we used electron cryo-microscopy (cryo-EM) to determine the binding sites of APN-1607 in the Alzheimer fold. We identified two major sites in the β-helix of PHFs and SFs and a third major site in the C-shaped cavity of SFs. In addition, we report that tau filaments from posterior cortical atrophy (PCA) and primary age-related tauopathy (PART) are identical to those from AD. In support, fluorescence labelling showed binding of APN-1607 to intraneuronal inclusions in AD, PART and PCA. Knowledge of the binding modes of APN-1607 to tau filaments may lead to the development of new ligands with increased specificity and binding activity. We show that cryo-EM can be used to identify the binding sites of small molecules in amyloid filaments.
History
DepositionMar 4, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 24, 2021Provider: repository / Type: Initial release
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Revision 1.0Mar 24, 2021Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
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Revision 1.0Mar 24, 2021Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.0Mar 24, 2021Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
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Revision 1.1Mar 31, 2021Group: Database references / Category: citation
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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
G: Microtubule-associated protein tau
H: Microtubule-associated protein tau
I: Microtubule-associated protein tau
J: Microtubule-associated protein tau


Theoretical massNumber of molelcules
Total (without water)459,19910
Polymers459,19910
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: microscopy
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area53030 Å2
ΔGint-149 kcal/mol
Surface area30520 Å2

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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.: 10 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P10636
Has protein modificationN

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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: Sarkosyl-insoluble fractions from primary age-related tauopathy brain
Type: TISSUE / Entity ID: all / Source: NATURAL
Source (natural)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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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
Image recordingElectron dose: 58 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.18.2_3874: / Classification: refinement
EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: 179.44 ° / Axial rise/subunit: 2.37 Å / Axial symmetry: C1
3D reconstructionResolution: 2.76 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 425943 / Symmetry type: HELICAL
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0065960
ELECTRON MICROSCOPYf_angle_d1.0427970
ELECTRON MICROSCOPYf_dihedral_angle_d21.203790
ELECTRON MICROSCOPYf_chiral_restr0.061890
ELECTRON MICROSCOPYf_plane_restr0.0041020

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