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Yorodumi- EMDB-26607: Structure of Type I Prion filaments from Gerstmann-Straussler-Sch... -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-26607 | |||||||||
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Title | Structure of Type I Prion filaments from Gerstmann-Straussler-Scheinker disease | |||||||||
Map data | ||||||||||
Sample |
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Keywords | Prion / PrP / GSS / filament / fibril / human brain derived / neurodegenerative / PROTEIN FIBRIL | |||||||||
Function / homology | Function and homology information positive regulation of glutamate receptor signaling pathway / negative regulation of amyloid precursor protein catabolic process / lamin binding / regulation of glutamate receptor signaling pathway / regulation of calcium ion import across plasma membrane / aspartic-type endopeptidase inhibitor activity / glycosaminoglycan binding / ATP-dependent protein binding / NCAM1 interactions / negative regulation of interleukin-17 production ...positive regulation of glutamate receptor signaling pathway / negative regulation of amyloid precursor protein catabolic process / lamin binding / regulation of glutamate receptor signaling pathway / regulation of calcium ion import across plasma membrane / aspartic-type endopeptidase inhibitor activity / glycosaminoglycan binding / ATP-dependent protein binding / NCAM1 interactions / negative regulation of interleukin-17 production / regulation of potassium ion transmembrane transport / type 5 metabotropic glutamate receptor binding / negative regulation of dendritic spine maintenance / cupric ion binding / negative regulation of protein processing / dendritic spine maintenance / negative regulation of calcineurin-NFAT signaling cascade / negative regulation of T cell receptor signaling pathway / Insertion of tail-anchored proteins into the endoplasmic reticulum membrane / negative regulation of interleukin-2 production / extrinsic component of membrane / negative regulation of amyloid-beta formation / negative regulation of activated T cell proliferation / cuprous ion binding / response to amyloid-beta / negative regulation of type II interferon production / negative regulation of long-term synaptic potentiation / intracellular copper ion homeostasis / positive regulation of protein targeting to membrane / long-term memory / response to cadmium ion / regulation of peptidyl-tyrosine phosphorylation / inclusion body / cellular response to copper ion / neuron projection maintenance / positive regulation of calcium-mediated signaling / tubulin binding / negative regulation of protein phosphorylation / molecular function activator activity / positive regulation of protein localization to plasma membrane / molecular condensate scaffold activity / protein destabilization / protein homooligomerization / negative regulation of DNA-binding transcription factor activity / terminal bouton / positive regulation of peptidyl-tyrosine phosphorylation / cellular response to amyloid-beta / positive regulation of neuron apoptotic process / cellular response to xenobiotic stimulus / signaling receptor activity / protein-folding chaperone binding / amyloid-beta binding / microtubule binding / protease binding / nuclear membrane / transmembrane transporter binding / response to oxidative stress / postsynapse / molecular adaptor activity / postsynaptic density / learning or memory / regulation of cell cycle / membrane raft / copper ion binding / external side of plasma membrane / intracellular membrane-bounded organelle / dendrite / protein-containing complex binding / negative regulation of apoptotic process / Golgi apparatus / cell surface / endoplasmic reticulum / extracellular exosome / identical protein binding / plasma membrane / cytosol / cytoplasm Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | helical reconstruction / cryo EM / Resolution: 3.29 Å | |||||||||
Authors | Ozcan KO / Hoq MR / Bharath SR / Jiang W | |||||||||
Funding support | United States, 2 items
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Citation | Journal: Acta Neuropathol / Year: 2022 Title: Cryo-EM structures of prion protein filaments from Gerstmann-Sträussler-Scheinker disease. Authors: Grace I Hallinan / Kadir A Ozcan / Md Rejaul Hoq / Laura Cracco / Frank S Vago / Sakshibeedu R Bharath / Daoyi Li / Max Jacobsen / Emma H Doud / Amber L Mosley / Anllely Fernandez / Holly J ...Authors: Grace I Hallinan / Kadir A Ozcan / Md Rejaul Hoq / Laura Cracco / Frank S Vago / Sakshibeedu R Bharath / Daoyi Li / Max Jacobsen / Emma H Doud / Amber L Mosley / Anllely Fernandez / Holly J Garringer / Wen Jiang / Bernardino Ghetti / Ruben Vidal / Abstract: Prion protein (PrP) aggregation and formation of PrP amyloid (APrP) are central events in the pathogenesis of prion diseases. In the dominantly inherited prion protein amyloidosis known as Gerstmann- ...Prion protein (PrP) aggregation and formation of PrP amyloid (APrP) are central events in the pathogenesis of prion diseases. In the dominantly inherited prion protein amyloidosis known as Gerstmann-Sträussler-Scheinker (GSS) disease, plaques made of PrP amyloid are present throughout the brain. The c.593t > c mutation in the prion protein gene (PRNP) results in a phenylalanine to serine amino acid substitution at PrP residue 198 (F198S) and causes the most severe amyloidosis among GSS variants. It has been shown that neurodegeneration in this disease is associated with the presence of extracellular APrP plaques and neuronal intracytoplasmic Tau inclusions, that have been shown to contain paired helical filaments identical to those found in Alzheimer disease. Using cryogenic electron microscopy (cryo-EM), we determined for the first time the structures of filaments of human APrP, isolated post-mortem from the brain of two symptomatic PRNP F198S mutation carriers. We report that in GSS (F198S) APrP filaments are composed of dimeric, trimeric and tetrameric left-handed protofilaments with their protomers sharing a common protein fold. The protomers in the cross-β spines consist of 62 amino acids and span from glycine 80 to phenylalanine 141, adopting a previously unseen spiral fold with a thicker outer layer and a thinner inner layer. Each protomer comprises nine short β-strands, with the β1 and β8 strands, as well as the β4 and β9 strands, forming a steric zipper. The data obtained by cryo-EM provide insights into the structural complexity of the PrP filament in a dominantly inherited human PrP amyloidosis. The novel findings highlight the urgency of extending our knowledge of the filaments' structures that may underlie distinct clinical and pathologic phenotypes of human neurodegenerative diseases. | |||||||||
History |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_26607.map.gz | 45.3 MB | EMDB map data format | |
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Header (meta data) | emd-26607-v30.xml emd-26607.xml | 18.7 KB 18.7 KB | Display Display | EMDB header |
Images | emd_26607.png | 69.5 KB | ||
Filedesc metadata | emd-26607.cif.gz | 5.6 KB | ||
Others | emd_26607_additional_1.map.gz emd_26607_half_map_1.map.gz emd_26607_half_map_2.map.gz | 24.1 MB 19 MB 19 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-26607 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-26607 | HTTPS FTP |
-Validation report
Summary document | emd_26607_validation.pdf.gz | 897.2 KB | Display | EMDB validaton report |
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Full document | emd_26607_full_validation.pdf.gz | 896.8 KB | Display | |
Data in XML | emd_26607_validation.xml.gz | 12.4 KB | Display | |
Data in CIF | emd_26607_validation.cif.gz | 14.4 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-26607 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-26607 | HTTPS FTP |
-Related structure data
Related structure data | 7umqMC 7un5C M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_26607.map.gz / Format: CCP4 / Size: 52.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||
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Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.078 Å | ||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Additional map: #1
File | emd_26607_additional_1.map | ||||||||||||
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Density Histograms |
-Half map: #2
File | emd_26607_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_26607_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
-Entire : Type I Prion protein filament from Gerstmann-Straussler-Scheinker...
Entire | Name: Type I Prion protein filament from Gerstmann-Straussler-Scheinker disease |
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Components |
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-Supramolecule #1: Type I Prion protein filament from Gerstmann-Straussler-Scheinker...
Supramolecule | Name: Type I Prion protein filament from Gerstmann-Straussler-Scheinker disease type: tissue / ID: 1 / Parent: 0 / Macromolecule list: all |
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Source (natural) | Organism: Homo sapiens (human) / Organ: Brain / Tissue: Cerebellum |
-Macromolecule #1: Major prion protein
Macromolecule | Name: Major prion protein / type: protein_or_peptide / ID: 1 / Number of copies: 10 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) / Organ: Brain / Tissue: Cerebellum |
Molecular weight | Theoretical: 6.219043 KDa |
Sequence | String: GWGQPHGGGW GQGGGTHSQW NKPSKPKTNM KHMAGAAAAG AVVGGLGGYV LGSAMSRPII HF UniProtKB: Major prion protein |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | helical reconstruction |
Aggregation state | filament |
-Sample preparation
Buffer | pH: 8 Component:
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Grid | Model: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Support film - Material: GRAPHENE OXIDE / Support film - topology: CONTINUOUS / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 10 sec. / Pretreatment - Atmosphere: AIR / Pretreatment - Pressure: 0.002 kPa Details: Glow discharged using PELCO easiGlow at 15 mA for 10 seconds. | ||||||||
Vitrification | Cryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 293 K / Instrument: GATAN CRYOPLUNGE 3 / Details: Plunge frozen in a BSL-2 hood. |
-Electron microscopy
Microscope | TFS KRIOS |
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Specialist optics | Energy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV |
Image recording | Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Number grids imaged: 1 / Number real images: 8600 / Average electron dose: 56.5 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.4 µm / Nominal magnification: 81000 |
Sample stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
-Image processing
Final reconstruction | Applied symmetry - Helical parameters - Δz: 4.82 Å Applied symmetry - Helical parameters - Δ&Phi: -0.92 ° Applied symmetry - Helical parameters - Axial symmetry: C2 (2 fold cyclic) Resolution.type: BY AUTHOR / Resolution: 3.29 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.1) / Number images used: 11305 |
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Startup model | Type of model: NONE |
Final angle assignment | Type: NOT APPLICABLE |
-Atomic model buiding 1
Refinement | Space: REAL / Protocol: AB INITIO MODEL |
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Output model | PDB-7umq: |