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- EMDB-42812: PNMA2 capsid, overall icosahedral map -

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Basic information

Entry
Database: EMDB / ID: EMD-42812
TitlePNMA2 capsid, overall icosahedral map
Map dataPNMA2 capsid, overall refinement, I4 symmetry
Sample
  • Complex: PNMA2 icosahedral capsid
    • Protein or peptide: Paraneoplastic antigen Ma2
Keywordscapsid / endogenous retrovirus-like particle / paraneoplasm / antigen / VIRUS LIKE PARTICLE
Function / homology: / : / PNMA N-terminal RRM-like domain / Paraneoplastic antigen Ma / PNMA / positive regulation of apoptotic process / nucleolus / Paraneoplastic antigen Ma2
Function and homology information
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsWilkinson ME / Madigan V / Zhang Y / Zhang F
Funding support United States, 2 items
OrganizationGrant numberCountry
Howard Hughes Medical Institute (HHMI) United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID) United States
CitationJournal: Proc Natl Acad Sci U S A / Year: 2024
Title: Human paraneoplastic antigen Ma2 (PNMA2) forms icosahedral capsids that can be engineered for mRNA delivery.
Authors: Victoria Madigan / Yugang Zhang / Rumya Raghavan / Max E Wilkinson / Guilhem Faure / Elena Puccio / Michael Segel / Blake Lash / Rhiannon K Macrae / Feng Zhang /
Abstract: A number of endogenous genes in the human genome encode retroviral -like proteins, which were domesticated from ancient retroelements. The paraneoplastic Ma antigen (PNMA) family members encode a - ...A number of endogenous genes in the human genome encode retroviral -like proteins, which were domesticated from ancient retroelements. The paraneoplastic Ma antigen (PNMA) family members encode a -like capsid domain, but their ability to assemble as capsids and traffic between cells remains mostly uncharacterized. Here, we systematically investigate human PNMA proteins and find that a number of PNMAs are secreted by human cells. We determine that PNMA2 forms icosahedral capsids efficiently but does not naturally encapsidate nucleic acids. We resolve the cryoelectron microscopy (cryo-EM) structure of PNMA2 and leverage the structure to design engineered PNMA2 (ePNMA2) particles with RNA packaging abilities. Recombinantly purified ePNMA2 proteins package mRNA molecules into icosahedral capsids and can function as delivery vehicles in mammalian cell lines, demonstrating the potential for engineered endogenous capsids as a nucleic acid therapy delivery modality.
History
DepositionNov 13, 2023-
Header (metadata) releaseMar 20, 2024-
Map releaseMar 20, 2024-
UpdateMar 20, 2024-
Current statusMar 20, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_42812.png

Downloads & links

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Map

FileDownload / File: emd_42812.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationPNMA2 capsid, overall refinement, I4 symmetry
Voxel sizeX=Y=Z: 0.9654 Å
Density
Contour LevelBy AUTHOR: 0.012
Minimum - Maximum-0.029693514 - 0.06099679
Average (Standard dev.)0.00025883262 (±0.0028936306)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 347.544 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_42812_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Refinement half-map 1

Fileemd_42812_half_map_1.map
AnnotationRefinement half-map 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Refinement half-map 2

Fileemd_42812_half_map_2.map
AnnotationRefinement half-map 2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : PNMA2 icosahedral capsid

EntireName: PNMA2 icosahedral capsid
Components
  • Complex: PNMA2 icosahedral capsid
    • Protein or peptide: Paraneoplastic antigen Ma2

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Supramolecule #1: PNMA2 icosahedral capsid

SupramoleculeName: PNMA2 icosahedral capsid / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 2.49 MDa

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Macromolecule #1: Paraneoplastic antigen Ma2

MacromoleculeName: Paraneoplastic antigen Ma2 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 41.557289 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MALALLEDWC RIMSVDEQKS LMVTGIPADF EEAEIQEVLQ ETLKSLGRYR LLGKIFRKQE NANAVLLELL EDTDVSAIPS EVQGKGGVW KVIFKTPNQD TEFLERLNLF LEKEGQTVSG MFRALGQEGV SPATVPCISP ELLAHLLGQA MAHAPQPLLP M RYRKLRVF ...String:
MALALLEDWC RIMSVDEQKS LMVTGIPADF EEAEIQEVLQ ETLKSLGRYR LLGKIFRKQE NANAVLLELL EDTDVSAIPS EVQGKGGVW KVIFKTPNQD TEFLERLNLF LEKEGQTVSG MFRALGQEGV SPATVPCISP ELLAHLLGQA MAHAPQPLLP M RYRKLRVF SGSAVPAPEE ESFEVWLEQA TEIVKEWPVT EAEKKRWLAE SLRGPALDLM HIVQADNPSI SVEECLEAFK QV FGSLESR RTAQVRYLKT YQEEGEKVSA YVLRLETLLR RAVEKRAIPR RIADQVRLEQ VMAGATLNQM LWCRLRELKD QGP PPSFLE LMKVIREEEE EEASFENESI EEPEERDGYG RWNHEGDD

UniProtKB: Paraneoplastic antigen Ma2

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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

Concentration1.5 mg/mL
BufferpH: 7.4 / Details: phosphate buffered saline, pH 7.4
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 60 sec. / Pretreatment - Atmosphere: AIR
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 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 opticsC2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal defocus max: 2.6 µm / Nominal defocus min: 1.0 µm / Nominal magnification: 130000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Number grids imaged: 1 / Number real images: 17600 / Average exposure time: 0.6 sec. / Average electron dose: 30.68 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 722571
Startup modelType of model: INSILICO MODEL
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 4.1)
Final reconstructionNumber classes used: 1 / Applied symmetry - Point group: I (icosahedral) / Resolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 4.1) / Number images used: 88320
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

2-f1


Chain - Source name: AlphaFold / Chain - Initial model type: in silico model
RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

PDB-8uyo:
Structure of a recombinant human PNMA2 capsid

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