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- EMDB-22368: Cryo-EM structure of MDA5-dsRNA in complex with TRIM65 PSpry doma... -

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Basic information

Entry
Database: EMDB / ID: EMD-22368
TitleCryo-EM structure of MDA5-dsRNA in complex with TRIM65 PSpry domain (Monomer)
Map dataThe map was postprocessed in Relion
Sample
  • Complex: Ternary complex of MDA5:dsRNA:TRIM65
    • RNA: RNA (5'-R(P*GP*AP*CP*UP*GP*AP*CP*UP*GP*AP*CP*UP*GP*A)-3')
    • RNA: RNA (5'-R(P*UP*CP*AP*GP*UP*CP*AP*GP*UP*CP*AP*GP*UP*C)-3')
    • Protein or peptide: Interferon-induced helicase C domain-containing protein 1
    • Protein or peptide: Tripartite motif-containing protein 65
  • Ligand: ZINC ION
  • Ligand: ADENOSINE-5'-DIPHOSPHATE
  • Ligand: TETRAFLUOROALUMINATE ION
  • Ligand: MAGNESIUM ION
KeywordsInnate immunity / Ubiquitin E3 ligase / dsRNA / RNA helicase / TRIM family / 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 / pattern recognition receptor activity / TRAF6 mediated IRF7 activation / negative regulation of viral genome replication / type I interferon-mediated signaling pathway ...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 / pattern recognition receptor activity / TRAF6 mediated IRF7 activation / negative regulation of viral genome replication / type I interferon-mediated signaling pathway / cellular response to exogenous dsRNA / cytoplasmic pattern recognition receptor signaling pathway / protein K63-linked ubiquitination / positive regulation of interferon-alpha production / antiviral innate immune response / TRAF6 mediated NF-kB activation / protein sumoylation / protein K48-linked ubiquitination / ribonucleoprotein complex binding / positive regulation of autophagy / positive regulation of interferon-beta production / Negative regulators of DDX58/IFIH1 signaling / response to virus / RING-type E3 ubiquitin transferase / DDX58/IFIH1-mediated induction of interferon-alpha/beta / cellular response to virus / negative regulation of inflammatory response / positive regulation of interleukin-6 production / SARS-CoV-1 activates/modulates innate immune responses / ubiquitin protein ligase activity / Ovarian tumor domain proteases / positive regulation of tumor necrosis factor production / double-stranded RNA binding / protein complex oligomerization / TRAF3-dependent IRF activation pathway / defense response to virus / RNA helicase activity / single-stranded RNA binding / Ub-specific processing proteases / RNA helicase / positive regulation of protein phosphorylation / 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. / Butyrophylin-like, SPRY domain / Caspase recruitment domain / 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. / Butyrophylin-like, SPRY domain / Caspase recruitment domain / Caspase recruitment domain / B-box zinc finger / B-Box-type zinc finger / B-box-type zinc finger / Zinc finger B-box type profile. / Helicase/UvrB, N-terminal / Type III restriction enzyme, res subunit / Zinc finger, C3HC4 RING-type / Zinc finger, C3HC4 type (RING finger) / SPRY domain / B30.2/SPRY domain / B30.2/SPRY domain profile. / SPRY domain / B30.2/SPRY domain superfamily / Domain in SPla and the RYanodine Receptor. / 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 / 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 / Concanavalin A-like lectin/glucanase domain superfamily / Zinc finger, RING/FYVE/PHD-type / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
E3 ubiquitin-protein ligase TRIM65 / Interferon-induced helicase C domain-containing protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.3 Å
AuthorsKato K / Ahmad S
Funding support United States, 1 items
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, 2020-
Header (metadata) releaseDec 9, 2020-
Map releaseDec 9, 2020-
UpdateMar 6, 2024-
Current statusMar 6, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.0212
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.0212
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7jl0
  • Surface level: 0.0212
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_22368.png

Downloads & links

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Map

FileDownload / File: emd_22368.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationThe map was postprocessed in Relion
Voxel sizeX=Y=Z: 1.03594 Å
Density
Contour LevelBy AUTHOR: 0.0212 / Movie #1: 0.0212
Minimum - Maximum-0.05318068 - 0.10763279
Average (Standard dev.)0.00018863358 (±0.0023229294)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 265.20065 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.035941406251.035941406251.03594140625
M x/y/z256256256
origin x/y/z0.0000.0000.000
length x/y/z265.201265.201265.201
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS256256256
D min/max/mean-0.0530.1080.000

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Supplemental data

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Sample components

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Entire : Ternary complex of MDA5:dsRNA:TRIM65

EntireName: Ternary complex of MDA5:dsRNA:TRIM65
Components
  • Complex: Ternary complex of MDA5:dsRNA:TRIM65
    • RNA: RNA (5'-R(P*GP*AP*CP*UP*GP*AP*CP*UP*GP*AP*CP*UP*GP*A)-3')
    • RNA: RNA (5'-R(P*UP*CP*AP*GP*UP*CP*AP*GP*UP*CP*AP*GP*UP*C)-3')
    • Protein or peptide: Interferon-induced helicase C domain-containing protein 1
    • Protein or peptide: Tripartite motif-containing protein 65
  • Ligand: ZINC ION
  • Ligand: ADENOSINE-5'-DIPHOSPHATE
  • Ligand: TETRAFLUOROALUMINATE ION
  • Ligand: MAGNESIUM ION

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Supramolecule #1: Ternary complex of MDA5:dsRNA:TRIM65

SupramoleculeName: Ternary complex of MDA5:dsRNA:TRIM65 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: RNA (5'-R(P*GP*AP*CP*UP*GP*AP*CP*UP*GP*AP*CP*UP*GP*A)-3')

MacromoleculeName: RNA (5'-R(P*GP*AP*CP*UP*GP*AP*CP*UP*GP*AP*CP*UP*GP*A)-3')
type: rna / ID: 1 / Number of copies: 1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 4.486731 KDa
SequenceString:
GACUGACUGA CUGA

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Macromolecule #2: RNA (5'-R(P*UP*CP*AP*GP*UP*CP*AP*GP*UP*CP*AP*GP*UP*C)-3')

MacromoleculeName: RNA (5'-R(P*UP*CP*AP*GP*UP*CP*AP*GP*UP*CP*AP*GP*UP*C)-3')
type: rna / ID: 2 / Number of copies: 1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 4.423667 KDa
SequenceString:
UCAGUCAGUC AGUC

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Macromolecule #3: Interferon-induced helicase C domain-containing protein 1

MacromoleculeName: Interferon-induced helicase C domain-containing protein 1
type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO / EC number: RNA helicase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 84.901695 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MGSDSDEENV AARASPEPEL QLRPYQMEVA QPALEGKNII ICLPTGSGKT RVAVYIAKDH LDKKKKASEP GKVIVLVNKV LLVEQLFRK EFQPFLKKWY RVIGLSGDTQ LKISFPEVVK SCDIIISTAQ ILENSLLNLE NGEDAGVQLS DFSLIIIDEC H HTNKEAVY ...String:
MGSDSDEENV AARASPEPEL QLRPYQMEVA QPALEGKNII ICLPTGSGKT RVAVYIAKDH LDKKKKASEP GKVIVLVNKV LLVEQLFRK EFQPFLKKWY RVIGLSGDTQ LKISFPEVVK SCDIIISTAQ ILENSLLNLE NGEDAGVQLS DFSLIIIDEC H HTNKEAVY NNIMRHYLMQ KLKNNRLKKE NKPVIPLPQI LGLTASPGVG GATKQAKAEE HILKLCANLD AFTIKTVKEN LD QLKNQIQ EPCKKFAIAD ATREDPFKEK LLEIMTRIQT YCQMSPMSDF GTQPYEQWAI QMEKKAAKEG NRKERVCAEH LRK YNEALQ INDTIRMIDA YTHLETFYNE EKDKKFAVIE DDSDEGGDDE YCDGDEDEDD LKKPLKLDET DRFLMTLFFE NNKM LKRLA ENPEYENEKL TKLRNTIMEQ YTRTEESARG IIFTKTRQSA YALSQWITEN EKFAEVGVKA HHLIGAGHSS EFKPM TQNE QKEVISKFRT GKINLLIATT VAEEGLDIKE CNIVIRYGLV TNEIAMVQAR GRARADESTY VLVAHSGSGV IERETV NDF REKMMYKAIH CVQNMKPEEY AHKILELQMQ SIMEKKMKTK RNIAKHYKNN PSLITFLCKN CSVLACSGED IHVIEKM HH VNMTPEFKEL YIVREKKTLQ KKCADYQING EIICKCGQAW GTMMVHKGLD LPCLKIRNFV VVFKNNSTKK QYKKWVEL P ITFPNLDYSE CCLFSDED

UniProtKB: Interferon-induced helicase C domain-containing protein 1

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Macromolecule #4: Tripartite motif-containing protein 65

MacromoleculeName: Tripartite motif-containing protein 65 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 21.643365 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
LAPVPSTVCP LRRKLWQNYR NLTFDPVSAN RHFYLSRQDQ QVKHLRQSRG PGGPGSFELW QVQCAQSFQA GHHYWEVRAS DHSVTLGVS YPQLPRSRLG PHTDNIGRGP SSWGLCVQED SLQAWHNGEA QRLPGVSGRL LGMDLDLASG CLTFYSLEPQ T QPLYTFHA LFNQPLTPVF WLLEGRTLTL CHQ

UniProtKB: E3 ubiquitin-protein ligase TRIM65

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Macromolecule #5: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 5 / Number of copies: 1 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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Macromolecule #6: ADENOSINE-5'-DIPHOSPHATE

MacromoleculeName: ADENOSINE-5'-DIPHOSPHATE / type: ligand / ID: 6 / Number of copies: 1 / Formula: ADP
Molecular weightTheoretical: 427.201 Da
Chemical component information

ChemComp-ADP:
ADENOSINE-5'-DIPHOSPHATE / ADP, energy-carrying molecule*YM / Adenosine diphosphate

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Macromolecule #7: TETRAFLUOROALUMINATE ION

MacromoleculeName: TETRAFLUOROALUMINATE ION / type: ligand / ID: 7 / Number of copies: 1 / Formula: ALF
Molecular weightTheoretical: 102.975 Da
Chemical component information

ChemComp-ALF:
TETRAFLUOROALUMINATE ION

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Macromolecule #8: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 8 / Number of copies: 1 / Formula: MG
Molecular weightTheoretical: 24.305 Da

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation statefilament

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Sample preparation

BufferpH: 7.5
GridDetails: unspecified
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 76.5 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER / Details: Featureless cylinder
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION
Final reconstructionResolution.type: BY AUTHOR / Resolution: 4.3 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 49051
FSC plot (resolution estimation)

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