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 Foundation
NNF17OC0030788
Denmark
Citation
Journal: 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.
Name: Paraneoplastic antigen Ma2 homolog / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)
Organism: Mus musculus (house mouse)
Molecular weight
Theoretical: 20.667789 KDa
Recombinant expression
Organism: Escherichia coli (E. coli)
Sequence
String:
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
-
Structure determination
Method
cryo EM
Processing
single particle reconstruction
Aggregation state
particle
-
Sample preparation
Concentration
1 mg/mL
Buffer
pH: 7.4 Component:
Concentration
Formula
Name
377.0 mM
Na2HPO4+7(H2O)
Sodium Phosphate Dibasic Heptahydrate
0.5 mM
(HO2CCH2)2NCH2CH2N(CH2CO2H)2
EDTAEthylenediaminetetraacetic acid
122.0 mM
NaH2PO4+H2O
Sodium Phosphate Monobasic Monohydrate
50.0 mM
NH2C(CH2OH)3
Tris
Grid
Model: 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.
Vitrification
Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 278 K / Instrument: FEI VITROBOT MARK IV
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Electron microscopy
Microscope
FEI TITAN KRIOS
Electron beam
Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Film 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 selection
Number selected: 47652
Startup model
Type of model: NONE
Initial angle assignment
Type: MAXIMUM LIKELIHOOD
Final 3D classification
Number classes: 4 / Software - Name: RELION (ver. 4) Details: Proceeded with 90 percent of capsids af classification
Final angle assignment
Type: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 4)
Final reconstruction
Number 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 model
Chain - Source name: AlphaFold / Chain - Initial model type: in silico model
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