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- PDB-7jl2: Cryo-EM structure of MDA5-dsRNA filament in complex with TRIM65 P... -

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Basic information

Entry
Database: PDB / ID: 7jl2
TitleCryo-EM structure of MDA5-dsRNA filament in complex with TRIM65 PSpry domain (Trimer)
Components
  • (RNA (44-MER)) x 2
  • Interferon-induced helicase C domain-containing protein 1
  • Tripartite motif-containing protein 65
KeywordsHYDROLASE/IMMUNE SYSTEM/RNA / RNA helicase / Ubiquitin E3 ligase / innate immunity / dsRNA / TRIM family / ATPase / HYDROLASE-IMMUNE SYSTEM-RNA complex
Function / homology
Function and homology information


positive regulation of protein oligomerization / MDA-5 signaling pathway / regulation of type III interferon production / detection of virus / NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10 / positive regulation of response to cytokine stimulus / Modulation of host responses by IFN-stimulated genes / TRAF6 mediated IRF7 activation / type I interferon-mediated signaling pathway / negative regulation of viral genome replication ...positive regulation of protein oligomerization / MDA-5 signaling pathway / regulation of type III interferon production / detection of virus / NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10 / positive regulation of response to cytokine stimulus / Modulation of host responses by IFN-stimulated genes / TRAF6 mediated IRF7 activation / type I interferon-mediated signaling pathway / negative regulation of viral genome replication / cytoplasmic pattern recognition receptor signaling pathway / pattern recognition receptor activity / cellular response to exogenous dsRNA / protein complex oligomerization / TRAF6 mediated NF-kB activation / positive regulation of interferon-alpha production / protein sumoylation / protein K63-linked ubiquitination / ribonucleoprotein complex binding / protein K48-linked ubiquitination / positive regulation of autophagy / antiviral innate immune response / positive regulation of interferon-beta production / Negative regulators of DDX58/IFIH1 signaling / RING-type E3 ubiquitin transferase / DDX58/IFIH1-mediated induction of interferon-alpha/beta / Evasion by RSV of host interferon responses / response to virus / cellular response to virus / positive regulation of interleukin-6 production / negative regulation of inflammatory response / positive regulation of tumor necrosis factor production / SARS-CoV-1 activates/modulates innate immune responses / ubiquitin protein ligase activity / Ovarian tumor domain proteases / double-stranded RNA binding / TRAF3-dependent IRF activation pathway / defense response to virus / single-stranded RNA binding / RNA helicase activity / Ub-specific processing proteases / RNA helicase / innate immune response / SARS-CoV-2 activates/modulates innate and adaptive immune responses / ATP hydrolysis activity / mitochondrion / DNA binding / RNA binding / zinc ion binding / nucleoplasm / ATP binding / identical protein binding / nucleus / cytosol / cytoplasm
Similarity search - Function
: / : / RIG-I-like receptor, C-terminal / RIG-I receptor C-terminal domain / RIG-I-like receptor, C-terminal regulatory domain / RIG-I-like receptor, C-terminal domain superfamily / : / C-terminal domain of RIG-I / RIG-I-like receptor (RLR) C-terminal regulatory (CTR) domain profile. / Caspase recruitment domain ...: / : / RIG-I-like receptor, C-terminal / RIG-I receptor C-terminal domain / RIG-I-like receptor, C-terminal regulatory domain / RIG-I-like receptor, C-terminal domain superfamily / : / C-terminal domain of RIG-I / RIG-I-like receptor (RLR) C-terminal regulatory (CTR) domain profile. / Caspase recruitment domain / Caspase recruitment domain / Helicase/UvrB, N-terminal / Butyrophylin-like, SPRY domain / Type III restriction enzyme, res subunit / B-box zinc finger / B-Box-type zinc finger / B-box-type zinc finger / Zinc finger B-box type profile. / Zinc finger, C3HC4 RING-type / Zinc finger, C3HC4 type (RING finger) / SPRY domain / B30.2/SPRY domain / B30.2/SPRY domain profile. / B30.2/SPRY domain superfamily / Domain in SPla and the RYanodine Receptor. / SPRY domain / Zinc finger, RING-type, conserved site / Zinc finger RING-type signature. / Death-like domain superfamily / Ring finger / Helicase conserved C-terminal domain / Zinc finger RING-type profile. / Zinc finger, RING-type / helicase superfamily c-terminal domain / Concanavalin A-like lectin/glucanase domain superfamily / Superfamilies 1 and 2 helicase C-terminal domain profile. / Superfamilies 1 and 2 helicase ATP-binding type-1 domain profile. / DEAD-like helicases superfamily / Helicase, C-terminal / Helicase superfamily 1/2, ATP-binding domain / Zinc finger, RING/FYVE/PHD-type / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
ADENOSINE-5'-DIPHOSPHATE / TETRAFLUOROALUMINATE ION / RNA / RNA (> 10) / E3 ubiquitin-protein ligase TRIM65 / Interferon-induced helicase C domain-containing protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 4.3 Å
AuthorsKato, K. / Ahmad, S. / Hur, S.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID) United States
CitationJournal: Mol Cell / Year: 2021
Title: Structural analysis of RIG-I-like receptors reveals ancient rules of engagement between diverse RNA helicases and TRIM ubiquitin ligases.
Authors: Kazuki Kato / Sadeem Ahmad / Zixiang Zhu / Janet M Young / Xin Mu / Sehoon Park / Harmit S Malik / Sun Hur /
Abstract: RNA helicases and E3 ubiquitin ligases mediate many critical functions in cells, but their actions have largely been studied in distinct biological contexts. Here, we uncover evolutionarily conserved ...RNA helicases and E3 ubiquitin ligases mediate many critical functions in cells, but their actions have largely been studied in distinct biological contexts. Here, we uncover evolutionarily conserved rules of engagement between RNA helicases and tripartite motif (TRIM) E3 ligases that lead to their functional coordination in vertebrate innate immunity. Using cryoelectron microscopy and biochemistry, we show that RIG-I-like receptors (RLRs), viral RNA receptors with helicase domains, interact with their cognate TRIM/TRIM-like E3 ligases through similar epitopes in the helicase domains. Their interactions are avidity driven, restricting the actions of TRIM/TRIM-like proteins and consequent immune activation to RLR multimers. Mass spectrometry and phylogeny-guided biochemical analyses further reveal that similar rules of engagement may apply to diverse RNA helicases and TRIM/TRIM-like proteins. Our analyses suggest not only conserved substrates for TRIM proteins but also, unexpectedly, deep evolutionary connections between TRIM proteins and RNA helicases, linking ubiquitin and RNA biology throughout animal evolution.
History
DepositionJul 29, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 9, 2020Provider: repository / Type: Initial release
Revision 1.0Dec 9, 2020Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Dec 9, 2020Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Dec 9, 2020Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.0Dec 9, 2020Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Dec 9, 2020Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.0Dec 9, 2020Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Dec 9, 2020Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.0Dec 9, 2020Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Dec 9, 2020Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Jan 20, 2021Group: Database references / Category: citation
Item: _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Feb 17, 2021Group: Database references / Category: citation
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Revision 1.3Mar 6, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.4Jun 4, 2025Group: Data collection / Structure summary / Category: em_admin / em_software / pdbx_entry_details
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Revision 1.1Jun 4, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Data processing / Experimental summary / Data content type: EM metadata / EM metadata / Category: em_admin / em_software / Data content type: EM metadata / EM metadata / Item: _em_admin.last_update / _em_software.name

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Structure visualization

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Assembly

Deposited unit
X: RNA (44-MER)
Y: RNA (44-MER)
A: Interferon-induced helicase C domain-containing protein 1
B: Tripartite motif-containing protein 65
C: Interferon-induced helicase C domain-containing protein 1
D: Tripartite motif-containing protein 65
E: Interferon-induced helicase C domain-containing protein 1
F: Tripartite motif-containing protein 65
hetero molecules


Theoretical massNumber of molelcules
Total (without water)349,67720
Polymers347,8178
Non-polymers1,86012
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: native gel electrophoresis
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area25250 Å2
ΔGint-209 kcal/mol
Surface area129790 Å2

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Components

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RNA chain , 2 types, 2 molecules XY

#1: RNA chain RNA (44-MER)


Mass: 14208.519 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)
#2: RNA chain RNA (44-MER)


Mass: 13973.247 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)

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Protein , 2 types, 6 molecules ACEBDF

#3: Protein Interferon-induced helicase C domain-containing protein 1 / Clinically amyopathic dermatomyositis autoantigen 140 kDa / CADM-140 autoantigen / Helicase with 2 ...Clinically amyopathic dermatomyositis autoantigen 140 kDa / CADM-140 autoantigen / Helicase with 2 CARD domains / Helicard / Interferon-induced with helicase C domain protein 1 / Melanoma differentiation-associated protein 5 / MDA-5 / Murabutide down-regulated protein / RIG-I-like receptor 2 / RLR-2 / RNA helicase-DEAD box protein 116 / IFIH1


Mass: 84901.695 Da / Num. of mol.: 3 / Fragment: UNP residues 287-1025
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IFIH1, MDA5, RH116 / Production host: Escherichia coli (E. coli) / References: UniProt: Q9BYX4, RNA helicase
#4: Protein Tripartite motif-containing protein 65 / TRIM65


Mass: 21643.365 Da / Num. of mol.: 3 / Fragment: TRIM65 PSpry domain (UNP residues 312-502)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TRIM65 / Production host: Escherichia coli (E. coli) / References: UniProt: Q6PJ69

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Non-polymers , 4 types, 12 molecules

#5: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Zn
#6: Chemical ChemComp-ADP / ADENOSINE-5'-DIPHOSPHATE


Mass: 427.201 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C10H15N5O10P2 / Comment: ADP, energy-carrying molecule*YM
#7: Chemical ChemComp-ALF / TETRAFLUOROALUMINATE ION


Mass: 102.975 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: AlF4
#8: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Mg

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Details

Has ligand of interestN
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: FILAMENT / 3D reconstruction method: helical reconstruction

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Sample preparation

ComponentName: Ternary complex of MDA5-dsRNA-TRIM65 / Type: COMPLEX / Entity ID: #1-#4 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportDetails: unspecified
VitrificationCryogen name: ETHANE

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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
Image recordingElectron dose: 72.8 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.18.2_3874: / Classification: refinement
EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: 86.9406 ° / Axial rise/subunit: 46.8426 Å / Axial symmetry: C1
3D reconstructionResolution: 4.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 15306 / Symmetry type: HELICAL
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00622730
ELECTRON MICROSCOPYf_angle_d0.7931119
ELECTRON MICROSCOPYf_dihedral_angle_d10.493774
ELECTRON MICROSCOPYf_chiral_restr0.0443548
ELECTRON MICROSCOPYf_plane_restr0.0043634

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