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Yorodumi- EMDB-12552: Straight filament from Alzheimer's disease with PET ligand APN-1607 -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-12552 | |||||||||||||||||||||
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Title | Straight filament from Alzheimer's disease with PET ligand APN-1607 | |||||||||||||||||||||
Map data | ||||||||||||||||||||||
Sample |
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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 / 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 / lipoprotein particle binding / dynactin binding / glial cell projection / negative regulation of mitochondrial membrane potential / 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 / Activation of AMPK downstream of NMDARs / regulation of microtubule cytoskeleton organization / supramolecular fiber organization / stress granule assembly / regulation of cellular response to heat / cytoplasmic microtubule organization / regulation of calcium-mediated signaling / positive regulation of microtubule polymerization / axon cytoplasm / somatodendritic compartment / cellular response to brain-derived neurotrophic factor stimulus / 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 / response to lead ion / synapse organization / microglial cell activation / Hsp90 protein binding / regulation of synaptic plasticity / PKR-mediated signaling / protein homooligomerization / memory / cellular response to reactive oxygen species / microtubule cytoskeleton organization / SH3 domain binding / cytoplasmic ribonucleoprotein granule / activation of cysteine-type endopeptidase activity involved in apoptotic process / neuron projection development / microtubule cytoskeleton / cell-cell signaling / protein-macromolecule adaptor activity / single-stranded DNA binding / cellular response to heat / actin binding / cell body / protein-folding chaperone binding / growth cone / microtubule binding / double-stranded DNA 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) / Human (human) | |||||||||||||||||||||
Method | helical reconstruction / cryo EM / Resolution: 3.55 Å | |||||||||||||||||||||
Authors | Shi Y / Murzin AG / Falcon B / Epstein A / Machin J / Tempest P / Newell KL / Vidal R / Garringer HJ / Sahara N ...Shi Y / Murzin AG / Falcon B / Epstein A / Machin J / Tempest P / Newell KL / Vidal R / Garringer HJ / Sahara N / Higuchi M / Ghetti B / Jang M / Scheres SHW / Goedert M | |||||||||||||||||||||
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_12552.map.gz | 24.3 MB | EMDB map data format | |
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Header (meta data) | emd-12552-v30.xml emd-12552.xml | 28 KB 28 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_12552_fsc.xml | 9.1 KB | Display | FSC data file |
Images | emd_12552.png | 71 KB | ||
Masks | emd_12552_msk_1.map | 64 MB | Mask map | |
Others | emd_12552_additional_1.map.gz emd_12552_additional_2.map.gz emd_12552_additional_3.map.gz emd_12552_additional_4.map.gz emd_12552_additional_5.map.gz emd_12552_additional_6.map.gz emd_12552_half_map_1.map.gz emd_12552_half_map_2.map.gz | 24.3 MB 24.3 MB 24.3 MB 24.3 MB 24.3 MB 24.3 MB 49.4 MB 49.4 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-12552 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-12552 | HTTPS FTP |
-Related structure data
Related structure data | 7nrxMC 7nrqC 7nrsC 7nrtC 7nrvC 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_12552.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Voxel size | X=Y=Z: 1.15 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_12552_msk_1.map | ||||||||||||
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-Additional map: For extra densities quantitation.
File | emd_12552_additional_1.map | ||||||||||||
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Annotation | For extra densities quantitation. | ||||||||||||
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-Additional map: For extra densities quantitation.
File | emd_12552_additional_2.map | ||||||||||||
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Annotation | For extra densities quantitation. | ||||||||||||
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-Additional map: For extra densities quantitation.
File | emd_12552_additional_3.map | ||||||||||||
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Annotation | For extra densities quantitation. | ||||||||||||
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-Additional map: For extra densities quantitation.
File | emd_12552_additional_4.map | ||||||||||||
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Annotation | For extra densities quantitation. | ||||||||||||
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-Additional map: For extra densities quantitation.
File | emd_12552_additional_5.map | ||||||||||||
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Annotation | For extra densities quantitation. | ||||||||||||
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-Additional map: For extra densities quantitation.
File | emd_12552_additional_6.map | ||||||||||||
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Annotation | For extra densities quantitation. | ||||||||||||
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-Half map: #1
File | emd_12552_half_map_1.map | ||||||||||||
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Density Histograms |
-Half map: #2
File | emd_12552_half_map_2.map | ||||||||||||
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-Sample components
-Entire : Sarkosyl-insoluble fractions from Alzheimer's disease with PET li...
Entire | Name: Sarkosyl-insoluble fractions from Alzheimer's disease with PET ligand APN-1607 |
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Components |
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-Supramolecule #1: Sarkosyl-insoluble fractions from Alzheimer's disease with PET li...
Supramolecule | Name: Sarkosyl-insoluble fractions from Alzheimer's disease with PET ligand APN-1607 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: Human (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 |
-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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Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy |
Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Average electron dose: 50.6 e/Å2 |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |