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- PDB-8wzx: Cryo-EM structure of the hamster prion 23-144 fibril at pH 3.7 -

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Basic information

Entry
Database: PDB / ID: 8wzx
TitleCryo-EM structure of the hamster prion 23-144 fibril at pH 3.7
ComponentsMajor prion protein
KeywordsPROTEIN FIBRIL / prion / 23-144 / hamster / PrP
Function / homology
Function and homology information


regulation of glutamate receptor signaling pathway / regulation of calcium ion import across plasma membrane / aspartic-type endopeptidase inhibitor activity / glycosaminoglycan binding / negative regulation of interleukin-17 production / regulation of potassium ion transmembrane transport / negative regulation of dendritic spine maintenance / type 5 metabotropic glutamate receptor binding / cupric ion binding / negative regulation of calcineurin-NFAT signaling cascade ...regulation of glutamate receptor signaling pathway / regulation of calcium ion import across plasma membrane / aspartic-type endopeptidase inhibitor activity / glycosaminoglycan binding / negative regulation of interleukin-17 production / regulation of potassium ion transmembrane transport / negative regulation of dendritic spine maintenance / type 5 metabotropic glutamate receptor binding / cupric ion binding / negative regulation of calcineurin-NFAT signaling cascade / negative regulation of interleukin-2 production / negative regulation of T cell receptor signaling pathway / cuprous ion binding / negative regulation of amyloid-beta formation / negative regulation of activated T cell proliferation / : / negative regulation of type II interferon production / positive regulation of protein targeting to membrane / side of membrane / inclusion body / cellular response to copper ion / neuron projection maintenance / molecular condensate scaffold activity / protein sequestering activity / negative regulation of protein phosphorylation / molecular function activator activity / positive regulation of protein localization to plasma membrane / protein destabilization / protein homooligomerization / terminal bouton / cellular response to amyloid-beta / positive regulation of neuron apoptotic process / positive regulation of peptidyl-tyrosine phosphorylation / cellular response to xenobiotic stimulus / signaling receptor activity / amyloid-beta binding / microtubule binding / nuclear membrane / response to oxidative stress / protease binding / amyloid fibril formation / learning or memory / regulation of cell cycle / cell cycle / membrane raft / copper ion binding / dendrite / protein-containing complex binding / negative regulation of apoptotic process / Golgi apparatus / cell surface / endoplasmic reticulum / identical protein binding / plasma membrane / 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 speciesMesocricetus auratus (golden hamster)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 2.88 Å
AuthorsLee, C.-H. / Saw, J.-E. / Chen, E. / Wang, C.-H. / Chen, R.
Funding support Taiwan, 3items
OrganizationGrant numberCountry
Ministry of Science and Technology (MoST, Taiwan)MOST 107-2113-M-001-033 Taiwan
Ministry of Science and Technology (MoST, Taiwan)MOST 108-2113-M-001-003 Taiwan
Ministry of Science and Technology (MoST, Taiwan)MOST 109-2113-M-001-001 Taiwan
CitationJournal: J Mol Biol / Year: 2024
Title: The Positively Charged Cluster in the N-terminal Disordered Region may Affect Prion Protein Misfolding: Cryo-EM Structure of Hamster PrP(23-144) Fibrils.
Authors: Chih-Hsuan Lee / Jing-Ee Saw / Eric H-L Chen / Chun-Hsiung Wang / Takayuki Uchihashi / Rita P-Y Chen /
Abstract: Prions, the misfolding form of prion proteins, are contagious proteinaceous macromolecules. Recent studies have shown that infectious prion fibrils formed in the brain and non-infectious fibrils ...Prions, the misfolding form of prion proteins, are contagious proteinaceous macromolecules. Recent studies have shown that infectious prion fibrils formed in the brain and non-infectious fibrils formed from recombinant prion protein in a partially denaturing condition have distinct structures. The amyloid core of the in vitro-prepared non-infectious fibrils starts at about residue 160, while that of infectious prion fibrils formed in the brain involves a longer sequence (residues ∼90-230) of structural conversion. The C-terminal truncated prion protein PrP(23-144) can form infectious fibrils under certain conditions and cause disease in animals. In this study, we used cryogenic electron microscopy (cryo-EM) to resolve the structure of hamster sHaPrP(23-144) fibrils prepared at pH 3.7. This 2.88 Å cryo-EM structure has an amyloid core covering residues 94-144. It comprises two protofilaments, each containing five β-strands arranged as a long hairpin plus an N-terminal β-strand. This N-terminal β-strand resides in a positively charged cluster region (named PCC2; sequence 96-111), which interacts with the turn region of the opposite protofilaments' hairpin to stabilize the fibril structure. Interestingly, this sHaPrP(23-144) fibril structure differs from a recently reported structure formed by the human or mouse counterpart at pH 6.5. Moreover, sHaPrP(23-144) fibrils have many structural features in common with infectious prions. Whether this structure is infectious remains to be determined. More importantly, the sHaPrP(23-144) structure is different from the sHaPrP(108-144) fibrils prepared in the same fibrillization buffer, indicating that the N-terminal disordered region, possibly the positively charged cluster, influences the misfolding pathway of the prion protein.
History
DepositionNov 2, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0May 1, 2024Provider: repository / Type: Initial release
Revision 1.1May 8, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.title / _citation_author.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Major prion protein
B: Major prion protein
C: Major prion protein
D: Major prion protein
E: Major prion protein
F: Major prion protein
G: Major prion protein
H: Major prion protein
I: Major prion protein
J: Major prion protein
K: Major prion protein
L: Major prion protein
M: Major prion protein
N: Major prion protein
O: Major prion protein
P: Major prion protein
Q: Major prion protein
R: Major prion protein
S: Major prion protein
T: Major prion protein


Theoretical massNumber of molelcules
Total (without water)247,53320
Polymers247,53320
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
Major prion protein


Mass: 12376.642 Da / Num. of mol.: 20
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mesocricetus auratus (golden hamster) / Gene: PRNP / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P04273

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: FILAMENT / 3D reconstruction method: helical reconstruction

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Sample preparation

ComponentName: hamster prion 23-144 fibril / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Mesocricetus auratus (golden hamster)
Source (recombinant)Organism: Escherichia coli BL21(DE3) (bacteria)
Buffer solutionpH: 3.7 / Details: 20 mM NaOAc, 140 mM NaCl
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2000 nm / Nominal defocus min: 1400 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM software
IDNameCategory
2EPUimage acquisition
4CTFFINDCTF correction
7Cootmodel fitting
12RELION3D reconstruction
13PHENIXmodel refinement
CTF correctionType: NONE
Helical symmerty
IDImage processing-IDAngular rotation/subunit (°)Axial rise/subunit (Å)Axial symmetry
11179.2172.38C1
21179.2172.38C1
3D reconstructionResolution: 2.88 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 288368 / Symmetry type: HELICAL
Atomic model buildingB value: 101.7 / Protocol: AB INITIO MODEL / Space: REAL

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