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- EMDB-51786: Cryo-EM Structure of human OAS2 Dimer -

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Basic information

Entry
Database: EMDB / ID: EMD-51786
TitleCryo-EM Structure of human OAS2 Dimer
Map data
Sample
  • Complex: OAS2 dimer with zinc
    • Protein or peptide: 2'-5'-oligoadenylate synthase 2
  • Ligand: ZINC ION
Keywordsnucleotidyltransferase / zinc / oligoadenylate synthetase / innate immunity / RNA BINDING PROTEIN
Function / homology
Function and homology information


regulation of lactation / 2'-5' oligoadenylate synthase / 2'-5'-oligoadenylate synthetase activity / interleukin-27-mediated signaling pathway / OAS antiviral response / RNA catabolic process / nucleobase-containing compound metabolic process / type I interferon-mediated signaling pathway / negative regulation of viral genome replication / RSV-host interactions ...regulation of lactation / 2'-5' oligoadenylate synthase / 2'-5'-oligoadenylate synthetase activity / interleukin-27-mediated signaling pathway / OAS antiviral response / RNA catabolic process / nucleobase-containing compound metabolic process / type I interferon-mediated signaling pathway / negative regulation of viral genome replication / RSV-host interactions / antiviral innate immune response / positive regulation of interferon-beta production / response to virus / Interferon gamma signaling / positive regulation of tumor necrosis factor production / Interferon alpha/beta signaling / double-stranded RNA binding / defense response to virus / defense response to bacterium / intracellular membrane-bounded organelle / perinuclear region of cytoplasm / nucleoplasm / ATP binding / metal ion binding / membrane / cytosol / cytoplasm
Similarity search - Function
2-5-oligoadenylate synthetase, N-terminal conserved site / 2'-5'-oligoadenylate synthases signature 1. / 2-5-oligoadenylate synthetase, C-terminal conserved site / 2'-5'-oligoadenylate synthetase 1, domain 2/C-terminal / 2'-5'-oligoadenylate synthetase 1, domain 2, C-terminus / 2'-5'-oligoadenylate synthases signature 2. / 2'-5'-oligoadenylate synthase N-terminal region profile. / 2-5OAS/ClassI-CCAase, nucleotidyltransferase domain / Polymerase, nucleotidyl transferase domain / Nucleotidyltransferase domain / Nucleotidyltransferase superfamily
Similarity search - Domain/homology
2'-5'-oligoadenylate synthase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsMerold VR / Lammens K / de Oliveira Mann CC
Funding support Germany, European Union, 3 items
OrganizationGrant numberCountry
German Research Foundation (DFG)369799452 Germany
German Research Foundation (DFG)458004906 Germany
European Research Council (ERC)101117085European Union
CitationJournal: Mol Cell / Year: 2025
Title: Structural basis for OAS2 regulation and its antiviral function.
Authors: Veronika Merold / Indra Bekere / Stefanie Kretschmer / Adrian F Schnell / Dorota Kmiec / Rinu Sivarajan / Katja Lammens / Rou Liu / Julia Mergner / Julia Teppert / Maximilian Hirschenberger ...Authors: Veronika Merold / Indra Bekere / Stefanie Kretschmer / Adrian F Schnell / Dorota Kmiec / Rinu Sivarajan / Katja Lammens / Rou Liu / Julia Mergner / Julia Teppert / Maximilian Hirschenberger / Alexander Henrici / Sarah Hammes / Kathrin Buder / Marcus Weitz / Karl Hackmann / Lars M Koenig / Andreas Pichlmair / Nadine Schwierz / Konstantin M J Sparrer / Min Ae Lee-Kirsch / Carina C de Oliveira Mann /
Abstract: Oligoadenylate synthetase (OAS) proteins are immune sensors for double-stranded RNA and are critical for restricting viruses. OAS2 comprises two OAS domains, only one of which can synthesize 2'-5'- ...Oligoadenylate synthetase (OAS) proteins are immune sensors for double-stranded RNA and are critical for restricting viruses. OAS2 comprises two OAS domains, only one of which can synthesize 2'-5'-oligoadenylates for RNase L activation. Existing structures of OAS1 provide a model for enzyme activation, but they do not explain how multiple OAS domains discriminate RNA length. Here, we discover that human OAS2 exists in an auto-inhibited state as a zinc-mediated dimer and present a mechanism for RNA length discrimination: the catalytically deficient domain acts as a molecular ruler that prevents autoreactivity to short RNAs. We demonstrate that dimerization and myristoylation localize OAS2 to Golgi membranes and that this is required for OAS2 activation and the restriction of viruses that exploit the endomembrane system for replication, e.g., coronaviruses. Finally, our results highlight the non-redundant role of OAS proteins and emphasize the clinical relevance of OAS2 by identifying a patient with a loss-of-function mutation associated with autoimmune disease.
History
DepositionOct 10, 2024-
Header (metadata) releaseMay 28, 2025-
Map releaseMay 28, 2025-
UpdateJun 18, 2025-
Current statusJun 18, 2025Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_51786.png

Downloads & links

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Map

FileDownload / File: emd_51786.map.gz / Format: CCP4 / Size: 22.2 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.06 Å/pix.
x 180 pix.
= 190.62 Å		1.06 Å/pix.
x 180 pix.
= 190.62 Å		1.06 Å/pix.
x 180 pix.
= 190.62 Å

Surface

Projections

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.059 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.513
Minimum - Maximum-3.0839794 - 5.307503
Average (Standard dev.)0.005493217 (±0.16481932)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions180180180
Spacing180180180
CellA=B=C: 190.62 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_51786_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_51786_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : OAS2 dimer with zinc

EntireName: OAS2 dimer with zinc
Components
  • Complex: OAS2 dimer with zinc
    • Protein or peptide: 2'-5'-oligoadenylate synthase 2
  • Ligand: ZINC ION

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Supramolecule #1: OAS2 dimer with zinc

SupramoleculeName: OAS2 dimer with zinc / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 163 KDa

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Macromolecule #1: 2'-5'-oligoadenylate synthase 2

MacromoleculeName: 2'-5'-oligoadenylate synthase 2 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: 2'-5' oligoadenylate synthase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 84.75093 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MGSHHHHHHS AALEVLFQGP MGNGESQLSS VPAQKLGWFI QEYLKPYEEC QTLIDEMVNT ICDVLQEPEQ FPLVQGVAIG GSYGRKTVL RGNSDGTLVL FFSDLKQFQD QKRSQRDILD KTGDKLKFCL FTKWLKNNFE IQKSLDGFTI QVFTKNQRIS F EVLAAFNA ...String:
MGSHHHHHHS AALEVLFQGP MGNGESQLSS VPAQKLGWFI QEYLKPYEEC QTLIDEMVNT ICDVLQEPEQ FPLVQGVAIG GSYGRKTVL RGNSDGTLVL FFSDLKQFQD QKRSQRDILD KTGDKLKFCL FTKWLKNNFE IQKSLDGFTI QVFTKNQRIS F EVLAAFNA LSLNDNPSPW IYRELKRSLD KTNASPGEFA VCFTELQQKF FDNRPGKLKD LILLIKHWHQ QCQKKIKDLP SL SPYALEL LTVYAWEQGC RKDNFDIAEG VRTVLELIKC QEKLCIYWMV NYNFEDETIR NILLHQLQSA RPVILDPVDP TNN VSGDKI CWQWLKKEAQ TWLTSPNLDN ELPAPSWNVL PAPLFTTPGH LLDKFIKEFL QPNKCFLEQI DSAVNIIRTF LKEN CFRQS TAKIQIVRGG STAKGTALKT GSDADLVVFH NSLKSYTSQK NERHKIVKEI HEQLKAFWRE KEEELEVSFE PPKWK APRV LSFSLKSKVL NESVSFDVLP AFNALGQLSS GSTPSPEVYA GLIDLYKSSD LPGGEFSTCF TVLQRNFIRS RPTKLK DLI RLVKHWYKEC ERKLKPKGSL PPKYALELLT IYAWEQGSGV PDFDTAEGFR TVLELVTQYQ QLCIFWKVNY NFEDETV RK FLLSQLQKTR PVILDPAEPT GDVGGGDRWC WHLLAKEAKE WLSSPCFKDG TGNPIPPWKV PTMQTPGSCG ARIHPIVN E MFSSRSHRIL NNNSKRNF

UniProtKB: 2'-5'-oligoadenylate synthase 2

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Macromolecule #2: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 2 / Number of copies: 1 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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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

Concentration0.6 mg/mL
BufferpH: 7.5
Component:
ConcentrationFormulaName
85.0 mMNaClNaCl
25.0 mMHEPESHEPES, pH7.5
GridModel: Quantifoil R2/1 / Material: COPPER / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE-PROPANE / Chamber humidity: 95 % / Chamber temperature: 288.15 K / Instrument: LEICA PLUNGER

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.9 µm / Nominal defocus min: 1.4000000000000001 µm
Sample stageCooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING ONLY
Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 532195
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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