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- PDB-7td6: aRML prion fibril -

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Basic information

Entry
Database: PDB / ID: 7td6
TitleaRML prion fibril
ComponentsMajor prion protein
KeywordsPROTEIN FIBRIL / infectious prion / amyloid / parallel in-register
Function / homology
Function and homology information


Insertion of tail-anchored proteins into the endoplasmic reticulum membrane / 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 / negative regulation of interleukin-17 production / ATP-dependent protein binding / regulation of potassium ion transmembrane transport ...Insertion of tail-anchored proteins into the endoplasmic reticulum membrane / 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 / negative regulation of interleukin-17 production / ATP-dependent protein binding / regulation of potassium ion transmembrane transport / negative regulation of dendritic spine maintenance / type 5 metabotropic glutamate receptor binding / cupric ion binding / nucleobase-containing compound metabolic process / response to copper ion / negative regulation of interleukin-2 production / negative regulation of calcineurin-NFAT signaling cascade / negative regulation of T cell receptor signaling pathway / negative regulation of amyloid-beta formation / cuprous ion binding / activation of protein kinase activity / negative regulation of activated T cell proliferation / negative regulation of long-term synaptic potentiation / response to amyloid-beta / negative regulation of type II interferon production / : / intracellular copper ion homeostasis / positive regulation of protein targeting to membrane / response to cadmium ion / side of membrane / inclusion body / regulation of peptidyl-tyrosine phosphorylation / cellular response to copper ion / neuron projection maintenance / molecular condensate scaffold activity / tubulin binding / protein sequestering activity / negative regulation of protein phosphorylation / 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 neuron apoptotic process / regulation of protein localization / positive regulation of peptidyl-tyrosine phosphorylation / cellular response to xenobiotic stimulus / signaling receptor activity / amyloid-beta binding / protein-folding chaperone binding / microtubule binding / nuclear membrane / response to oxidative stress / protease binding / mitochondrial outer membrane / transmembrane transporter binding / postsynaptic density / learning or memory / molecular adaptor activity / copper ion binding / membrane raft / intracellular membrane-bounded organelle / dendrite / protein-containing complex binding / negative regulation of apoptotic process / Golgi apparatus / cell surface / endoplasmic reticulum / membrane / identical protein binding / metal ion 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 speciesMus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3 Å
AuthorsHoyt, F. / Standke, H.G. / Artikis, E. / Caughey, B. / Kraus, A.
Funding support2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)A1000580
Other private
Citation
Journal: Nat Commun / Year: 2022
Title: Cryo-EM structure of anchorless RML prion reveals variations in shared motifs between distinct strains.
Authors: Forrest Hoyt / Heidi G Standke / Efrosini Artikis / Cindi L Schwartz / Bryan Hansen / Kunpeng Li / Andrew G Hughson / Matteo Manca / Olivia R Thomas / Gregory J Raymond / Brent Race / Gerald ...Authors: Forrest Hoyt / Heidi G Standke / Efrosini Artikis / Cindi L Schwartz / Bryan Hansen / Kunpeng Li / Andrew G Hughson / Matteo Manca / Olivia R Thomas / Gregory J Raymond / Brent Race / Gerald S Baron / Byron Caughey / Allison Kraus /
Abstract: Little is known about the structural basis of prion strains. Here we provide a high (3.0 Å) resolution cryo-electron microscopy-based structure of infectious brain-derived fibrils of the mouse ...Little is known about the structural basis of prion strains. Here we provide a high (3.0 Å) resolution cryo-electron microscopy-based structure of infectious brain-derived fibrils of the mouse anchorless RML scrapie strain which, like the recently determined hamster 263K strain, has a parallel in-register β-sheet-based core. Several structural motifs are shared between these ex vivo prion strains, including an amino-proximal steric zipper and three β-arches. However, detailed comparisons reveal variations in these shared structural topologies and other features. Unlike 263K and wildtype RML prions, the anchorless RML prions lack glycophosphatidylinositol anchors and are severely deficient in N-linked glycans. Nonetheless, the similarity of our anchorless RML structure to one reported for wildtype RML prion fibrils in an accompanying paper indicates that these post-translational modifications do not substantially alter the amyloid core conformation. This work demonstrates both common and divergent structural features of prion strains at the near-atomic level.
#1: Journal: 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
DepositionDec 30, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 20, 2022Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)140,0425
Polymers140,0425
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
d_1ens_1chain "1"
d_2ens_1chain "A"
d_3ens_1chain "B"
d_4ens_1chain "C"
d_5ens_1chain "D"

NCS domain segments:
Dom-IDComponent-IDEns-IDBeg label comp-IDEnd label comp-IDLabel asym-IDLabel seq-ID
d_11ens_1GLYSERA1 - 138
d_21ens_1GLYSERB1 - 138
d_31ens_1GLYSERC1 - 138
d_41ens_1GLYSERD1 - 138
d_51ens_1GLYSERE1 - 138

NCS oper:
IDCodeMatrixVector
1given(0.999930241786, 0.0118107884642, 0.000129761689572), (-0.0118108179567, 0.999930223654, 0.000228916130534), (-0.000127048955282, -0.000230432753447, 0.99999996538)-2.42415973316, 2.36725224975, 4.95855819759
2given(0.999953377356, -0.00965558606535, 0.000113012258933), (0.00965563059222, 0.999953303181, -0.000400319437432), (-0.000109141662838, 0.000401391978106, 0.999999913486)1.90621393929, -1.85414969503, -4.98787989468
3given(0.999739912446, 0.0228050701433, 0.000190363497964), (-0.0228052176602, 0.999739597036, 0.000812505659014), (-0.0001717846782, -0.00081663561741, 0.999999651798)-4.61368631497, 4.50126924992, 9.97021760135
4given(0.999430716705, 0.0337354990601, 0.000398257560786), (-0.0337360928339, 0.999429507206, 0.00159253431087), (-0.00034430541797, -0.00160506336173, 0.999998652612)-6.80679289904, 6.61359256863, 15.0771851828

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Components

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


Mass: 28008.393 Da / Num. of mol.: 5 / Source method: isolated from a natural source
Details: proteinase-K resistant aRML prion fibril ordered core encompasses residues 93-230
Source: (natural) Mus musculus (house mouse) / References: UniProt: P04925

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Experimental details

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Experiment

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

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Sample preparation

ComponentName: aRML prion / Type: COMPLEX / Details: anchorless RML prion fibril / Entity ID: all / Source: NATURAL
Molecular weightExperimental value: NO
Source (natural)Organism: Mus musculus (house mouse) / Tissue: brain-derived
Buffer solutionpH: 7.4
SpecimenConc.: 0.4 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: purified aRML prion fibrils
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: C-flat-1.2/1.3
VitrificationCryogen name: ETHANE

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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: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Nominal magnification: 81000 X / Nominal defocus max: 2700 nm / Nominal defocus min: 500 nm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

Software
NameVersionClassification
phenix.real_space_refine1.19_4092refinement
PHENIX1.19_4092refinement
EM software
IDNameVersionCategory
1RELION3.1particle selection
2SerialEMimage acquisition
4CTFFIND4.1CTF correction
7Cootmodel fitting
9RELION3.1initial Euler assignment
10RELION3.1final Euler assignment
11RELION3.1classification
13PHENIXmodel refinement
14REFMACmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 135939
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 15857 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 102.8 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00195710
ELECTRON MICROSCOPYf_angle_d0.56977720
ELECTRON MICROSCOPYf_chiral_restr0.0487780
ELECTRON MICROSCOPYf_plane_restr0.00151020
ELECTRON MICROSCOPYf_dihedral_angle_d16.47332115
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDRefine-IDTypeRms dev position (Å)
ens_1d_2AELECTRON MICROSCOPYNCS constraints0.000496377761546
ens_1d_3AELECTRON MICROSCOPYNCS constraints0.0950938382349
ens_1d_4AELECTRON MICROSCOPYNCS constraints0.000496311178137
ens_1d_5AELECTRON MICROSCOPYNCS constraints0.0951478641837

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