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- EMDB-19024: Structure of the PNMA2 capsid -

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Basic information

Entry
Database: EMDB / ID: EMD-19024
TitleStructure of the PNMA2 capsid
Map data
Sample
  • Complex: Structure of the PNMA2 capsid
    • Protein or peptide: Paraneoplastic antigen Ma2 homolog
KeywordsEndogenous retrovirus. PNMA2 / PNMA / Paraneoplastic syndrome / Paraneoplastic antigen Ma2 / VLP. / VIRUS LIKE PARTICLE
Function / homology: / : / PNMA N-terminal RRM-like domain / Paraneoplastic antigen Ma / PNMA / nucleolus / Paraneoplastic antigen Ma2 homolog
Function and homology information
Biological speciesMus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsErlendsson S / Xu J / Shepherd JD / Briggs JAG
Funding support United States, United Kingdom, Denmark, 3 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)NIH R01 NS115716 United States
Medical Research Council (MRC, United Kingdom)MC_UP_1201/16 United Kingdom
Novo Nordisk FoundationNNF17OC0030788 Denmark
CitationJournal: Cell / Year: 2024
Title: PNMA2 forms immunogenic non-enveloped virus-like capsids associated with paraneoplastic neurological syndrome.
Authors: Junjie Xu / Simon Erlendsson / Manvendra Singh / G Aaron Holling / Matthew Regier / Iosune Ibiricu / Jenifer Einstein / Michael P Hantak / Gregory S Day / Amanda L Piquet / Tammy L Smith / ...Authors: Junjie Xu / Simon Erlendsson / Manvendra Singh / G Aaron Holling / Matthew Regier / Iosune Ibiricu / Jenifer Einstein / Michael P Hantak / Gregory S Day / Amanda L Piquet / Tammy L Smith / Stacey L Clardy / Alexandra M Whiteley / Cédric Feschotte / John A G Briggs / Jason D Shepherd /
Abstract: The paraneoplastic Ma antigen (PNMA) proteins are associated with cancer-induced paraneoplastic syndromes that present with an autoimmune response and neurological symptoms. Why PNMA proteins are ...The paraneoplastic Ma antigen (PNMA) proteins are associated with cancer-induced paraneoplastic syndromes that present with an autoimmune response and neurological symptoms. Why PNMA proteins are associated with this severe autoimmune disease is unclear. PNMA genes are predominantly expressed in the central nervous system and are ectopically expressed in some tumors. We show that PNMA2, which has been co-opted from a Ty3 retrotransposon, encodes a protein that is released from cells as non-enveloped virus-like capsids. Recombinant PNMA2 capsids injected into mice induce autoantibodies that preferentially bind external "spike" PNMA2 capsid epitopes, whereas a capsid-assembly-defective PNMA2 protein is not immunogenic. PNMA2 autoantibodies in cerebrospinal fluid of patients with anti-Ma2 paraneoplastic disease show similar preferential binding to spike capsid epitopes. PNMA2 capsid-injected mice develop learning and memory deficits. These observations suggest that PNMA2 capsids act as an extracellular antigen, capable of generating an autoimmune response that results in neurological deficits.
History
DepositionDec 2, 2023-
Header (metadata) releaseFeb 14, 2024-
Map releaseFeb 14, 2024-
UpdateFeb 28, 2024-
Current statusFeb 28, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_19024.png

Downloads & links

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Map

FileDownload / File: emd_19024.map.gz / Format: CCP4 / Size: 512 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.832 Å
Density
Contour LevelBy AUTHOR: 0.018
Minimum - Maximum-0.058151893 - 0.12559474
Average (Standard dev.)0.00037100576 (±0.003483039)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions512512512
Spacing512512512
CellA=B=C: 425.984 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: #1

Fileemd_19024_additional_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_19024_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_19024_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Structure of the PNMA2 capsid

EntireName: Structure of the PNMA2 capsid
Components
  • Complex: Structure of the PNMA2 capsid
    • Protein or peptide: Paraneoplastic antigen Ma2 homolog

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Supramolecule #1: Structure of the PNMA2 capsid

SupramoleculeName: Structure of the PNMA2 capsid / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Details: T=1 icosahedral mPNMA2 capsid consisting of 60 PNMA2 molecules
Source (natural)Organism: Mus musculus (house mouse)

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Macromolecule #1: Paraneoplastic antigen Ma2 homolog

MacromoleculeName: Paraneoplastic antigen Ma2 homolog / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 20.667789 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
LLPVKYCKMR IFSGSTAAAP EEEPFEVWLE QATEIAKEWP IPEAEKKRWV AESLRGPALD LMHIVQADNP SISVGECLEA FKQVFGSTE SRRTSQVKYL RTYQQEGEKI SAYVLRLETL LRRAVEKRAI PRNIADQVRL EQVMAGANLG NVLWCRLQEL K DQGPLPTF LQLMKVIREE EE

UniProtKB: Paraneoplastic antigen Ma2 homolog

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration1 mg/mL
BufferpH: 7.4
Component:
ConcentrationFormulaName
377.0 mMNa2HPO4+7(H2O)Sodium Phosphate Dibasic Heptahydrate
0.5 mM(HO2CCH2)2NCH2CH2N(CH2CO2H)2EDTAEthylenediaminetetraacetic acid
122.0 mMNaH2PO4+H2OSodium Phosphate Monobasic Monohydrate
50.0 mMNH2C(CH2OH)3Tris
GridModel: Quantifoil R2/2 / Material: GOLD / Mesh: 300 / Support film - Material: CARBON / Support film - topology: CONTINUOUS / Support film - Film thickness: 200 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 35 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 278 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal defocus max: 4.0 µm / Nominal defocus min: 0.5 µm / Nominal magnification: 96000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Image recordingFilm or detector model: FEI FALCON III (4k x 4k) / Detector mode: COUNTING / Digitization - Dimensions - Width: 4096 pixel / Digitization - Dimensions - Height: 4096 pixel / Number real images: 3005 / Average exposure time: 40.0 sec. / Average electron dose: 40.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 47652
Startup modelType of model: NONE
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final 3D classificationNumber classes: 4 / Software - Name: RELION (ver. 4)
Details: Proceeded with 90 percent of capsids af classification
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 4)
Final reconstructionNumber classes used: 1 / Applied symmetry - Point group: I (icosahedral) / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 4) / Number images used: 35420

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Atomic model buiding 1

Initial modelChain - Source name: AlphaFold / Chain - Initial model type: in silico model
RefinementSpace: REAL / Overall B value: 147
Output model

PDB-8rb3:
Structure of the PNMA2 capsid

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