+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-12550 | |||||||||||||||||||||
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Title | Straight filament from primary age-related tauopathy brain | |||||||||||||||||||||
Map data | The consensus map. The calibrated pixel size was used in post-processing procedure of RELION. | |||||||||||||||||||||
Sample |
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Keywords | Tau filament / PROTEIN FIBRIL | |||||||||||||||||||||
Function / homology | Function and homology information plus-end-directed organelle transport along microtubule / histone-dependent DNA binding / neurofibrillary tangle assembly / positive regulation of diacylglycerol kinase activity / axonal transport / 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 / histone-dependent DNA binding / neurofibrillary tangle assembly / positive regulation of diacylglycerol kinase activity / axonal transport / 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 / negative regulation of kinase activity / regulation of long-term synaptic depression / negative regulation of tubulin deacetylation / generation of neurons / rRNA metabolic process / internal protein amino acid acetylation / regulation of chromosome organization / regulation of mitochondrial fission / axonal transport of mitochondrion / intracellular distribution of mitochondria / axon development / central nervous system neuron development / regulation of microtubule polymerization / apolipoprotein binding / microtubule polymerization / lipoprotein particle binding / minor groove of adenine-thymine-rich DNA binding / dynactin binding / glial cell projection / negative regulation of mitochondrial membrane potential / protein polymerization / axolemma / negative regulation of mitochondrial fission / Caspase-mediated cleavage of cytoskeletal proteins / regulation of microtubule polymerization or depolymerization / positive regulation of axon extension / regulation of microtubule cytoskeleton organization / Activation of AMPK downstream of NMDARs / regulation of cellular response to heat / positive regulation of protein localization / cytoplasmic microtubule organization / stress granule assembly / supramolecular fiber organization / regulation of calcium-mediated signaling / axon cytoplasm / somatodendritic compartment / positive regulation of microtubule polymerization / synapse assembly / cellular response to brain-derived neurotrophic factor stimulus / 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 / response to lead ion / microglial cell activation / synapse organization / Hsp90 protein binding / protein homooligomerization / PKR-mediated signaling / regulation of synaptic plasticity / : / memory / SH3 domain binding / microtubule cytoskeleton organization / cytoplasmic ribonucleoprotein granule / cellular response to reactive oxygen species / microtubule cytoskeleton / neuron projection development / cell-cell signaling / single-stranded DNA binding / protein-folding chaperone binding / actin binding / protein-macromolecule adaptor activity / cellular response to heat / double-stranded DNA binding / growth cone / cell body / microtubule binding / microtubule / sequence-specific DNA binding / amyloid fibril formation / dendritic spine / learning or memory / nuclear speck / neuron projection / membrane raft / axon / negative regulation of gene expression / neuronal cell body / DNA damage response / dendrite / protein kinase binding / enzyme binding / mitochondrion / DNA binding Similarity search - Function | |||||||||||||||||||||
Biological species | Homo sapiens (human) | |||||||||||||||||||||
Method | helical reconstruction / cryo EM / Resolution: 2.68 Å | |||||||||||||||||||||
Authors | Shi Y / Murzin AG | |||||||||||||||||||||
Funding support | United Kingdom, European Union, United States, Japan, 6 items
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Citation | Journal: 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 |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | EM map: SurfViewMolmilJmol/JSmol |
Supplemental images |
-Downloads & links
-EMDB archive
Map data | emd_12550.map.gz | 110.9 MB | EMDB map data format | |
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Header (meta data) | emd-12550-v30.xml emd-12550.xml | 19.2 KB 19.2 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_12550_fsc.xml | 11.7 KB | Display | FSC data file |
Images | emd_12550.png | 112.9 KB | ||
Masks | emd_12550_msk_1.map | 137.1 MB | Mask map | |
Filedesc metadata | emd-12550.cif.gz | 5.4 KB | ||
Others | emd_12550_additional_1.map.gz emd_12550_additional_2.map.gz emd_12550_half_map_1.map.gz emd_12550_half_map_2.map.gz | 110.5 MB 110.3 MB 107.7 MB 107.7 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-12550 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-12550 | HTTPS FTP |
-Validation report
Summary document | emd_12550_validation.pdf.gz | 928.8 KB | Display | EMDB validaton report |
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Full document | emd_12550_full_validation.pdf.gz | 928.3 KB | Display | |
Data in XML | emd_12550_validation.xml.gz | 20.2 KB | Display | |
Data in CIF | emd_12550_validation.cif.gz | 25.4 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-12550 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-12550 | HTTPS FTP |
-Related structure data
Related structure data | 7nrsMC 7nrtMC 7nrqC 7nrvC 7nrxC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_12550.map.gz / Format: CCP4 / Size: 137.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Annotation | The consensus map. The calibrated pixel size was used in post-processing procedure of RELION. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 0.82 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Mask #1
File | emd_12550_msk_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Additional map: Conformation 1.
File | emd_12550_additional_1.map | ||||||||||||
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Annotation | Conformation 1. | ||||||||||||
Projections & Slices |
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Density Histograms |
-Additional map: Conformation 2.
File | emd_12550_additional_2.map | ||||||||||||
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Annotation | Conformation 2. | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_12550_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #2
File | emd_12550_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
-Entire : Sarkosyl-insoluble fractions from primary age-related tauopathy brain
Entire | Name: Sarkosyl-insoluble fractions from primary age-related tauopathy brain |
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Components |
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-Supramolecule #1: Sarkosyl-insoluble fractions from primary age-related tauopathy brain
Supramolecule | Name: Sarkosyl-insoluble fractions from primary age-related tauopathy brain type: tissue / ID: 1 / Parent: 0 / Macromolecule list: all |
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Source (natural) | Organism: Homo sapiens (human) |
-Macromolecule #1: Microtubule-associated protein tau
Macromolecule | Name: Microtubule-associated protein tau / type: protein_or_peptide / ID: 1 / Number of copies: 10 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 45.919871 KDa |
Sequence | String: MAEPRQEFEV MEDHAGTYGL GDRKDQGGYT MHQDQEGDTD AGLKESPLQT PTEDGSEEPG SETSDAKSTP TAEDVTAPLV DEGAPGKQA AAQPHTEIPE GTTAEEAGIG DTPSLEDEAA GHVTQARMVS KSKDGTGSDD KKAKGADGKT KIATPRGAAP P GQKGQANA ...String: MAEPRQEFEV MEDHAGTYGL GDRKDQGGYT MHQDQEGDTD AGLKESPLQT PTEDGSEEPG SETSDAKSTP TAEDVTAPLV DEGAPGKQA AAQPHTEIPE GTTAEEAGIG DTPSLEDEAA GHVTQARMVS KSKDGTGSDD KKAKGADGKT KIATPRGAAP P GQKGQANA TRIPAKTPPA PKTPPSSGEP PKSGDRSGYS SPGSPGTPGS RSRTPSLPTP PTREPKKVAV VRTPPKSPSS AK SRLQTAP VPMPDLKNVK SKIGSTENLK HQPGGGKVQI INKKLDLSNV QSKCGSKDNI KHVPGGGSVQ IVYKPVDLSK VTS KCGSLG NIHHKPGGGQ VEVKSEKLDF KDRVQSKIGS LDNITHVPGG GNKKIETHKL TFRENAKAKT DHGAEIVYKS PVVS GDTSP RHLSNVSSTG SIDMVDSPQL ATLADEVSAS LAKQGL UniProtKB: Microtubule-associated protein tau |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | helical reconstruction |
Aggregation state | filament |
-Sample preparation
Buffer | pH: 7.5 |
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Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Average electron dose: 58.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |