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Yorodumi- PDB-7un5: Structure of Type II Prion filaments from Gerstmann-Straussler-Sc... -
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-Basic information
Entry | Database: PDB / ID: 7un5 | |||||||||
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Title | Structure of Type II Prion filaments from Gerstmann-Straussler-Scheinker disease | |||||||||
Components | Major prion protein | |||||||||
Keywords | PROTEIN FIBRIL / Prion / PrP / GSS / filament / fibril / human brain derived / neurodegenerative | |||||||||
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 / regulation of potassium ion transmembrane transport / 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 / regulation of potassium ion transmembrane transport / negative regulation of interleukin-17 production / NCAM1 interactions / negative regulation of dendritic spine maintenance / type 5 metabotropic glutamate receptor binding / cupric ion binding / negative regulation of protein processing / negative regulation of calcineurin-NFAT signaling cascade / dendritic spine maintenance / negative regulation of interleukin-2 production / negative regulation of T cell receptor signaling pathway / Insertion of tail-anchored proteins into the endoplasmic reticulum membrane / extrinsic component of membrane / cuprous ion binding / negative regulation of amyloid-beta formation / negative regulation of activated T cell proliferation / : / 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 / tubulin binding / negative regulation of protein phosphorylation / molecular condensate scaffold activity / molecular function activator activity / positive regulation of protein localization to plasma membrane / protein destabilization / protein homooligomerization / negative regulation of DNA-binding transcription factor activity / terminal bouton / cellular response to amyloid-beta / positive regulation of peptidyl-tyrosine phosphorylation / positive regulation of neuron apoptotic process / cellular response to xenobiotic stimulus / signaling receptor activity / amyloid-beta binding / protein-folding chaperone binding / microtubule binding / protease binding / nuclear membrane / postsynapse / cell cycle / response to oxidative stress / transmembrane transporter binding / 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 / cytoplasm / cytosol Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | ELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 3.13 Å | |||||||||
Authors | Ozcan, K.A. / Hoq, M.R. / Bharath, S.R. / Jiang, W. | |||||||||
Funding support | United States, 2items
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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
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 7un5.cif.gz | 102.9 KB | Display | PDBx/mmCIF format |
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PDB format | pdb7un5.ent.gz | 80.8 KB | Display | PDB format |
PDBx/mmJSON format | 7un5.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 7un5_validation.pdf.gz | 1.1 MB | Display | wwPDB validaton report |
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Full document | 7un5_full_validation.pdf.gz | 1.1 MB | Display | |
Data in XML | 7un5_validation.xml.gz | 30.2 KB | Display | |
Data in CIF | 7un5_validation.cif.gz | 42.4 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/un/7un5 ftp://data.pdbj.org/pub/pdb/validation_reports/un/7un5 | HTTPS FTP |
-Related structure data
Related structure data | 26613MC 7umqC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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-Components
#1: Protein | Mass: 6219.043 Da / Num. of mol.: 10 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Organ: Brain / Tissue: Cerebellum / References: UniProt: P04156 |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: FILAMENT / 3D reconstruction method: helical reconstruction |
-Sample preparation
Component | Name: Type II Prion protein filament from Gerstmann-Straussler-Scheinker disease Type: TISSUE / Entity ID: all / Source: NATURAL | ||||||||||||||||
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Source (natural) | Organism: Homo sapiens (human) / Organ: Brain / Tissue: Cerebellum | ||||||||||||||||
Buffer solution | pH: 8 | ||||||||||||||||
Buffer component |
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Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES | ||||||||||||||||
Specimen support | Details: Glow discharged using PELCO easiGlow at 15 mA for 10 seconds. Grid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3 | ||||||||||||||||
Vitrification | Instrument: GATAN CRYOPLUNGE 3 / Cryogen name: ETHANE / Humidity: 95 % / Chamber temperature: 293 K / Details: Plunge frozen in a BSL-2 hood |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: TFS KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELD / Nominal magnification: 81000 X / Nominal defocus max: 2000 nm / Nominal defocus min: 400 nm / Cs: 2.7 mm |
Specimen holder | Cryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER |
Image recording | Electron dose: 56.5 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 8600 |
EM imaging optics | Energyfilter name: GIF Bioquantum / Energyfilter slit width: 20 eV |
-Processing
EM software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
Helical symmerty | Angular rotation/subunit: -0.94 ° / Axial rise/subunit: 4.83 Å / Axial symmetry: C1 | ||||||||||||||||||||||||
3D reconstruction | Resolution: 3.13 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 19341 / Symmetry type: HELICAL | ||||||||||||||||||||||||
Atomic model building | Protocol: AB INITIO MODEL / Space: REAL | ||||||||||||||||||||||||
Refinement | Cross valid method: NONE Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2 | ||||||||||||||||||||||||
Displacement parameters | Biso mean: 99.08 Å2 | ||||||||||||||||||||||||
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