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- PDB-7lna: Infectious mammalian prion fibril (263K scrapie) -

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Basic information

Entry
Database: PDB / ID: 7lna
TitleInfectious mammalian prion fibril (263K scrapie)
ComponentsMajor prion protein
KeywordsPROTEIN FIBRIL / infectious mammalian prion / templating / glycosylated glycophophatidlyinositol-anchored amyloid / PIRIBS
Function / homology
Function and homology information


aspartic-type endopeptidase inhibitor activity / regulation of calcium ion import across plasma membrane / positive regulation of glutamate receptor signaling pathway / glycosaminoglycan binding / type 5 metabotropic glutamate receptor binding / negative regulation of interleukin-17 production / cupric ion binding / regulation of potassium ion transmembrane transport / negative regulation of dendritic spine maintenance / negative regulation of calcineurin-NFAT signaling cascade ...aspartic-type endopeptidase inhibitor activity / regulation of calcium ion import across plasma membrane / positive regulation of glutamate receptor signaling pathway / glycosaminoglycan binding / type 5 metabotropic glutamate receptor binding / negative regulation of interleukin-17 production / cupric ion binding / regulation of potassium ion transmembrane transport / negative regulation of dendritic spine maintenance / negative regulation of calcineurin-NFAT signaling cascade / negative regulation of interleukin-2 production / negative regulation of T cell receptor signaling pathway / negative regulation of activated T cell proliferation / negative regulation of amyloid-beta formation / negative regulation of type II interferon production / cuprous ion binding / positive regulation of protein targeting to membrane / side of membrane / inclusion body / neuron projection maintenance / positive regulation of calcium-mediated signaling / molecular function activator activity / cellular response to copper ion / positive regulation of protein localization to plasma membrane / molecular condensate scaffold activity / protein homooligomerization / protein destabilization / cellular response to xenobiotic stimulus / cellular response to amyloid-beta / terminal bouton / positive regulation of neuron apoptotic process / signaling receptor activity / presynapse / amyloid-beta binding / response to oxidative stress / protease binding / nuclear membrane / microtubule binding / amyloid fibril formation / learning or memory / regulation of cell cycle / intracellular signal transduction / membrane raft / copper ion binding / dendrite / negative regulation of apoptotic process / protein-containing complex binding / cell surface / endoplasmic reticulum / negative regulation of transcription by RNA polymerase II / Golgi apparatus / identical protein binding / plasma membrane / cytosol
Similarity search - Function
Prion, copper binding octapeptide repeat / Copper binding octapeptide repeat region / Major prion protein N-terminal domain / Major prion protein bPrPp - N terminal / Prion protein signature 1. / Prion protein signature 2. / 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 / single particle reconstruction / cryo EM / Resolution: 3.14 Å
AuthorsKraus, A. / Hoyt, F. / Schwartz, C.L. / Hansen, B. / Hughson, A.G. / Artikis, E. / Race, B. / Caughey, B.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)AI000580 United States
Other private United States
CitationJournal: Mol Cell / Year: 2021
Title: High-resolution structure and strain comparison of infectious mammalian prions.
Authors: Allison Kraus / Forrest Hoyt / Cindi L Schwartz / Bryan Hansen / Efrosini Artikis / Andrew G Hughson / Gregory J Raymond / Brent Race / Gerald S Baron / Byron Caughey /
Abstract: Within the extensive range of self-propagating pathologic protein aggregates of mammals, prions are the most clearly infectious (e.g., ∼10 lethal doses per milligram). The structures of such lethal ...Within the extensive range of self-propagating pathologic protein aggregates of mammals, prions are the most clearly infectious (e.g., ∼10 lethal doses per milligram). The structures of such lethal assemblies of PrP molecules have been poorly understood. Here we report a near-atomic core structure of a brain-derived, fully infectious prion (263K strain). Cryo-electron microscopy showed amyloid fibrils assembled with parallel in-register intermolecular β sheets. Each monomer provides one rung of the ordered fibril core, with N-linked glycans and glycolipid anchors projecting outward. Thus, single monomers form the templating surface for incoming monomers at fibril ends, where prion growth occurs. Comparison to another prion strain (aRML) revealed major differences in fibril morphology but, like 263K, an asymmetric fibril cross-section without paired protofilaments. These findings provide structural insights into prion propagation, strains, species barriers, and membrane pathogenesis. This structure also helps frame considerations of factors influencing the relative transmissibility of other pathologic amyloids.
History
DepositionFeb 6, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 1, 2021Provider: repository / Type: Initial release
Revision 1.1Sep 8, 2021Group: Database references / Category: citation / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Nov 17, 2021Group: Database references / Category: citation / Item: _citation.journal_volume / _citation.page_first
Revision 1.3Nov 6, 2024Group: Data collection / Refinement description / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / pdbx_entry_details / pdbx_modification_feature / refine / struct_ncs_dom_lim
Item: _em_admin.last_update / _refine.ls_d_res_high ..._em_admin.last_update / _refine.ls_d_res_high / _refine.ls_d_res_low / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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Structure visualization

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Structure viewerMolecule:
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Assembly

Deposited unit
A: Major prion protein
B: Major prion protein
C: Major prion protein


Theoretical massNumber of molelcules
Total (without water)48,7923
Polymers48,7923
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: microscopy
TypeNameSymmetry operationNumber
identity operation1_5551
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12A
22C
13B
23C

NCS domain segments:

Component-ID: _ / Beg auth comp-ID: THR / Beg label comp-ID: THR / End auth comp-ID: ASP / End label comp-ID: ASP / Refine code: _ / Auth seq-ID: 95 - 227 / Label seq-ID: 6 - 138

Dom-IDEns-IDAuth asym-IDLabel asym-ID
11AA
21BB
12AA
22CC
13BB
23CC

NCS ensembles :
ID
1
2
3

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Components

#1: Protein Major prion protein / PrP / PrP27-30 / PrP33-35C


Mass: 16264.101 Da / Num. of mol.: 3 / Source method: isolated from a natural source
Details: Protease-resistant glycosylated, glycophophatidlyinositol-anchored infectious prion amyloid core (inclusive of residues 90-231).
Source: (natural) Mesocricetus auratus (golden hamster) / Organ: brain / References: UniProt: P04273
Has protein modificationY

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Experimental details

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Experiment

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

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Sample preparation

ComponentName: infectious mammalian prion fibril (263K scrapie) / Type: COMPLEX
Details: Purified from brains of hamsters with clinical scrapie prion disease.
Entity ID: all / Source: NATURAL
Molecular weightExperimental value: NO
Source (natural)Organism: Mesocricetus auratus (golden hamster) / Organ: brain / Tissue: brain
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportDetails: Solarus 950 (Gatan, Pleasanton CA) / Grid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: C-flat-1.2/1.3
VitrificationInstrument: LEICA EM GP / Cryogen name: ETHANE / Humidity: 90 % / Chamber temperature: 295 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: OTHER
Electron lensMode: BRIGHT FIELD
Specimen holderCryogen: NITROGEN
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

SoftwareName: REFMAC / Version: 5.8.0258 / Classification: refinement
EM software
IDNameVersionCategoryDetails
1RELION3.1particle selection
2SerialEMimage acquisition
4CTFFIND4.1CTF correction
7Coot0.9.2premodel fitting
8PHENIX1.19model fitting
10PHENIX1.19model refinement
11REFMAC5model refinement
12RELION3.1initial Euler assignment
13RELION3.1final Euler assignment
14RELION3.1classification
15RELION3.13D reconstructionRELION was used for 2D and 3D classification of particles, refinement, Bayesian polishing and post-processing with a soft-edged mask.
Image processingDetails: Processing and reconstruction was conducted in Relion as per Scheres, Acta Cryst. (2020). D76, 94-101
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 337368
Details: Filament start and end positions were picked manually in RELION. Particles were extracted with an interbox distance of 14.7A along the filament axis.
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.14 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 15884 / Algorithm: FOURIER SPACE
Details: Auto-refinement was then performed while optimizing the helical twist and rise. Auto-refinement with refinement of twist and rise yielded a final map with a twist of -0.847 degree and rise ...Details: Auto-refinement was then performed while optimizing the helical twist and rise. Auto-refinement with refinement of twist and rise yielded a final map with a twist of -0.847 degree and rise of 4.874 angstrom. Iterative cycles of CTF refinement, Bayesian polishing, and auto refinement were used until resolution estimates stabilized. Post processing in RELION was performed with a soft-edged mask representing 10% of the central Z length of the fibril. Sharpening was applied with a B-factor of -31 square angstrom.
Symmetry type: POINT
Atomic model buildingProtocol: AB INITIO MODEL / Space: RECIPROCAL
RefinementResolution: 3.14→3.14 Å / Cor.coef. Fo:Fc: 0.808 / ESU R: 0.544
Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
RfactorNum. reflection% reflection
Rwork0.42912 --
obs0.42912 31660 100 %
Solvent computationSolvent model: PARAMETERS FOR MASK CACLULATION
Displacement parametersBiso mean: 39.924 Å2
Baniso -1Baniso -2Baniso -3
1-6.31 Å2-0.49 Å2-0.68 Å2
2--0.56 Å20.19 Å2
3----6.87 Å2
Refinement stepCycle: 1 / Total: 3171
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
ELECTRON MICROSCOPYr_bond_refined_d0.0120.0123249
ELECTRON MICROSCOPYr_bond_other_d
ELECTRON MICROSCOPYr_angle_refined_deg0.9521.6554395
ELECTRON MICROSCOPYr_angle_other_deg
ELECTRON MICROSCOPYr_dihedral_angle_1_deg6.3565384
ELECTRON MICROSCOPYr_dihedral_angle_2_deg37.98823.333198
ELECTRON MICROSCOPYr_dihedral_angle_3_deg15.79215543
ELECTRON MICROSCOPYr_dihedral_angle_4_deg19.3071518
ELECTRON MICROSCOPYr_chiral_restr0.0450.2414
ELECTRON MICROSCOPYr_gen_planes_refined0.0040.022565
ELECTRON MICROSCOPYr_gen_planes_other
ELECTRON MICROSCOPYr_nbd_refined
ELECTRON MICROSCOPYr_nbd_other
ELECTRON MICROSCOPYr_nbtor_refined
ELECTRON MICROSCOPYr_nbtor_other
ELECTRON MICROSCOPYr_xyhbond_nbd_refined
ELECTRON MICROSCOPYr_xyhbond_nbd_other
ELECTRON MICROSCOPYr_metal_ion_refined
ELECTRON MICROSCOPYr_metal_ion_other
ELECTRON MICROSCOPYr_symmetry_vdw_refined
ELECTRON MICROSCOPYr_symmetry_vdw_other
ELECTRON MICROSCOPYr_symmetry_hbond_refined
ELECTRON MICROSCOPYr_symmetry_hbond_other
ELECTRON MICROSCOPYr_symmetry_metal_ion_refined
ELECTRON MICROSCOPYr_symmetry_metal_ion_other
ELECTRON MICROSCOPYr_mcbond_it041554
ELECTRON MICROSCOPYr_mcbond_other
ELECTRON MICROSCOPYr_mcangle_it061932
ELECTRON MICROSCOPYr_mcangle_other
ELECTRON MICROSCOPYr_scbond_it041695
ELECTRON MICROSCOPYr_scbond_other
ELECTRON MICROSCOPYr_scangle_it
ELECTRON MICROSCOPYr_scangle_other
ELECTRON MICROSCOPYr_long_range_B_refined070.6929372
ELECTRON MICROSCOPYr_long_range_B_other
ELECTRON MICROSCOPYr_rigid_bond_restr
ELECTRON MICROSCOPYr_sphericity_free
ELECTRON MICROSCOPYr_sphericity_bonded
Refine LS restraints NCS

Refine-ID: ELECTRON MICROSCOPY / Type: interatomic distance / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A61220
12B61220
21A61200
22C61200
31B61200.01
32C61200.01
LS refinement shellResolution: 3.1→3.181 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0 0 -
Rwork0.57 2326 -
obs--100 %

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