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- PDB-8rb3: Structure of the PNMA2 capsid -

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Basic information

Entry
Database: PDB / ID: 8rb3
TitleStructure of the PNMA2 capsid
ComponentsParaneoplastic antigen Ma2 homolog
KeywordsVIRUS LIKE PARTICLE / Endogenous retrovirus. PNMA2 / PNMA / Paraneoplastic syndrome / Paraneoplastic antigen Ma2 / VLP.
Function / homologyParaneoplastic antigen Ma / : / : / PNMA / PNMA N-terminal RRM-like domain / nucleolus / Paraneoplastic antigen Ma2 homolog
Function and homology information
Biological speciesMus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsErlendsson, S. / Xu, J. / Shepherd, J.D. / Briggs, J.A.G.
Funding support United States, United Kingdom, Denmark, 3items
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, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 14, 2024Provider: repository / Type: Initial release
Revision 1.1Feb 28, 2024Group: Database references / Category: citation / Item: _citation.journal_volume / _citation.page_first

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Paraneoplastic antigen Ma2 homolog


Theoretical massNumber of molelcules
Total (without water)20,6681
Polymers20,6681
Non-polymers00
Water00
1
A: Paraneoplastic antigen Ma2 homolog
x 60


Theoretical massNumber of molelcules
Total (without water)1,240,06760
Polymers1,240,06760
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
point symmetry operation59
MethodUCSF CHIMERA

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Components

#1: Protein Paraneoplastic antigen Ma2 homolog


Mass: 20667.789 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Pnma2 / Production host: Escherichia coli (E. coli) / References: UniProt: Q8BHK0

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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: Structure of the PNMA2 capsid / Type: COMPLEX
Details: T=1 icosahedral mPNMA2 capsid consisting of 60 PNMA2 molecules
Entity ID: all / Source: RECOMBINANT
Molecular weightUnits: MEGADALTONS / Experimental value: NO
Source (natural)Organism: Mus musculus (house mouse)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.4
Buffer component
IDConc.NameFormulaBuffer-ID
1377 mMSodium Phosphate Dibasic HeptahydrateNa2HPO4+7(H2O)1
20.5 mMEDTA(HO2CCH2)2NCH2CH2N(CH2CO2H)21
3122 mMSodium Phosphate Monobasic MonohydrateNaH2PO4+H2O1
450 mMTrisNH2C(CH2OH)31
SpecimenConc.: 1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportFilm material: CARBON / Grid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R2/2
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 278 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: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 96000 X / Nominal defocus max: 4000 nm / Nominal defocus min: 500 nm / Cs: 2.7 mm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 40 sec. / Electron dose: 40 e/Å2 / Detector mode: COUNTING / Film or detector model: FEI FALCON III (4k x 4k) / Num. of real images: 3005
Image scansWidth: 4096 / Height: 4096

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Processing

EM software
IDNameVersionCategory
1RELION4particle selection
2EPUimage acquisition
4CTFFIND4.1CTF correction
7UCSF ChimeraX1.15model fitting
10RELION4final Euler assignment
11RELION4classification
12RELION43D reconstruction
13Coot0.9model refinement
14PHENIX1.20.1model refinement
15UCSF ChimeraX1.15model refinement
16ISOLDEmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 47652
SymmetryPoint symmetry: I (icosahedral)
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 35420 / Algorithm: FOURIER SPACE / Num. of class averages: 1 / Symmetry type: POINT
Atomic model buildingB value: 147 / Space: REAL
Atomic model buildingSource name: AlphaFold / Type: in silico model

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