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- EMDB-26607: Structure of Type I Prion filaments from Gerstmann-Straussler-Sch... -

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Entry
Database: EMDB / ID: EMD-26607
TitleStructure of Type I Prion filaments from Gerstmann-Straussler-Scheinker disease
Map data
Sample
  • Tissue: Type I Prion protein filament from Gerstmann-Straussler-Scheinker disease
    • Protein or peptide: Major prion protein
KeywordsPrion / 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 / regulation of potassium ion transmembrane transport / NCAM1 interactions ...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 / NCAM1 interactions / negative regulation of interleukin-17 production / 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 / postsynapse / microtubule binding / nuclear membrane / protease binding / response to oxidative stress / transmembrane transporter binding / molecular adaptor activity / postsynaptic density / learning or memory / regulation of cell cycle / membrane raft / cell cycle / 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
Prion protein signature 1. / Prion protein signature 2. / Major prion protein N-terminal domain / Major prion protein bPrPp - N terminal / Prion protein / Major prion protein / Prion/Doppel protein, beta-ribbon domain / Prion/Doppel beta-ribbon domain superfamily / Prion/Doppel alpha-helical domain
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
Methodhelical reconstruction / cryo EM / Resolution: 3.29 Å
AuthorsOzcan KO / Hoq MR / Bharath SR / Jiang W
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute on Aging (NIH/NIA) United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS) United States
CitationJournal: 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
DepositionApr 7, 2022-
Header (metadata) releaseJul 27, 2022-
Map releaseJul 27, 2022-
UpdateMar 27, 2024-
Current statusMar 27, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_26607.png

Downloads & links

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Map

FileDownload / File: emd_26607.map.gz / Format: CCP4 / Size: 52.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.078 Å
Density
Contour LevelBy AUTHOR: 3.63
Minimum - Maximum-8.687884 - 11.865424000000001
Average (Standard dev.)0.000000000004449 (±1.0)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions240240240
Spacing240240240
CellA=B=C: 258.72 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: #1

Fileemd_26607_additional_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_26607_half_map_1.map
Projections & Slices
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Histogram

Histogram (log scale)

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Half map: #1

Fileemd_26607_half_map_2.map
Projections & Slices
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Sample components

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Entire : Type I Prion protein filament from Gerstmann-Straussler-Scheinker...

EntireName: Type I Prion protein filament from Gerstmann-Straussler-Scheinker disease
Components
  • Tissue: Type I Prion protein filament from Gerstmann-Straussler-Scheinker disease
    • Protein or peptide: Major prion protein

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Supramolecule #1: Type I Prion protein filament from Gerstmann-Straussler-Scheinker...

SupramoleculeName: Type I Prion protein filament from Gerstmann-Straussler-Scheinker disease
type: tissue / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human) / Organ: Brain / Tissue: Cerebellum

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Macromolecule #1: Major prion protein

MacromoleculeName: Major prion protein / type: protein_or_peptide / ID: 1 / Number of copies: 10 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human) / Organ: Brain / Tissue: Cerebellum
Molecular weightTheoretical: 6.219043 KDa
SequenceString:
GWGQPHGGGW GQGGGTHSQW NKPSKPKTNM KHMAGAAAAG AVVGGLGGYV LGSAMSRPII HF

UniProtKB: Major prion protein

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Experimental details

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Structure determination

Methodcryo EM
Processinghelical reconstruction
Aggregation statefilament

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Sample preparation

BufferpH: 8
Component:
ConcentrationName
30.0 mMTris-HCl
120.0 mMNaCl
0.02 %A8-35
GridModel: 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.
VitrificationCryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 293 K / Instrument: GATAN CRYOPLUNGE 3 / Details: Plunge frozen in a BSL-2 hood.

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Electron microscopy

MicroscopeTFS KRIOS
Specialist opticsEnergy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV
Image recordingFilm 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 beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination 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 stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied 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
Startup modelType of model: NONE
Final angle assignmentType: NOT APPLICABLE

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: AB INITIO MODEL
Output model

PDB-7umq:
Structure of Type I Prion filaments from Gerstmann-Straussler-Scheinker disease

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