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- EMDB-30785: K63-polyUb MDA5CARDs complex -

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Basic information

Entry
Database: EMDB / ID: EMD-30785
TitleK63-polyUb MDA5CARDs complex
Map data
Sample
  • Complex: k63polyUb bound MDA5 CARDs complex
    • Complex: k63polyUb
      • Protein or peptide: Interferon-induced helicase C domain-containing protein 1
      • Protein or peptide: Ubiquitin
    • Complex: MDA5 CARDs
Keywordssignaling complex / IMMUNE SYSTEM
Function / homology
Function and homology information


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 / hypothalamus gonadotrophin-releasing hormone neuron development / female meiosis I / positive regulation of protein monoubiquitination / mitochondrion transport along microtubule / pattern recognition receptor activity ...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 / hypothalamus gonadotrophin-releasing hormone neuron development / female meiosis I / positive regulation of protein monoubiquitination / mitochondrion transport along microtubule / pattern recognition receptor activity / fat pad development / TRAF6 mediated IRF7 activation / cytoplasmic pattern recognition receptor signaling pathway / negative regulation of viral genome replication / type I interferon-mediated signaling pathway / female gonad development / cellular response to exogenous dsRNA / seminiferous tubule development / male meiosis I / positive regulation of interferon-alpha production / positive regulation of intrinsic apoptotic signaling pathway by p53 class mediator / TRAF6 mediated NF-kB activation / protein sumoylation / ribonucleoprotein complex binding / regulation of neuron apoptotic process / regulation of proteasomal protein catabolic process / antiviral innate immune response / energy homeostasis / Maturation of protein E / Maturation of protein E / ER Quality Control Compartment (ERQC) / Myoclonic epilepsy of Lafora / IRAK2 mediated activation of TAK1 complex / Alpha-protein kinase 1 signaling pathway / FLT3 signaling by CBL mutants / IRAK1 recruits IKK complex / IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation / Prevention of phagosomal-lysosomal fusion / Glycogen synthesis / IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation / Regulation of TBK1, IKKε (IKBKE)-mediated activation of IRF3, IRF7 / Endosomal Sorting Complex Required For Transport (ESCRT) / TICAM1,TRAF6-dependent induction of TAK1 complex / Membrane binding and targetting of GAG proteins / Regulation of TBK1, IKKε-mediated activation of IRF3, IRF7 upon TLR3 ligation / Negative regulation of FLT3 / Constitutive Signaling by NOTCH1 HD Domain Mutants / PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1 / Regulation of FZD by ubiquitination / TICAM1-dependent activation of IRF3/IRF7 / positive regulation of interferon-beta production / NOTCH2 Activation and Transmission of Signal to the Nucleus / p75NTR recruits signalling complexes / APC/C:Cdc20 mediated degradation of Cyclin B / Downregulation of ERBB4 signaling / TRAF6-mediated induction of TAK1 complex within TLR4 complex / TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling / APC-Cdc20 mediated degradation of Nek2A / Regulation of innate immune responses to cytosolic DNA / NF-kB is activated and signals survival / InlA-mediated entry of Listeria monocytogenes into host cells / Regulation of pyruvate metabolism / VLDLR internalisation and degradation / Downregulation of ERBB2:ERBB3 signaling / NRIF signals cell death from the nucleus / Pexophagy / Activated NOTCH1 Transmits Signal to the Nucleus / Regulation of PTEN localization / Regulation of BACH1 activity / Synthesis of active ubiquitin: roles of E1 and E2 enzymes / TICAM1, RIP1-mediated IKK complex recruitment / Translesion synthesis by REV1 / MAP3K8 (TPL2)-dependent MAPK1/3 activation / Translesion synthesis by POLK / neuron projection morphogenesis / Downregulation of TGF-beta receptor signaling / Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE) / Translesion synthesis by POLI / PINK1-PRKN Mediated Mitophagy / IKK complex recruitment mediated by RIP1 / Regulation of activated PAK-2p34 by proteasome mediated degradation / JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 / Gap-filling DNA repair synthesis and ligation in GG-NER / Josephin domain DUBs / InlB-mediated entry of Listeria monocytogenes into host cell / regulation of mitochondrial membrane potential / TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) / positive regulation of protein ubiquitination / TNFR1-induced NF-kappa-B signaling pathway / N-glycan trimming in the ER and Calnexin/Calreticulin cycle / Autodegradation of Cdh1 by Cdh1:APC/C / APC/C:Cdc20 mediated degradation of Securin / Regulation of NF-kappa B signaling / SCF-beta-TrCP mediated degradation of Emi1 / Asymmetric localization of PCP proteins / TCF dependent signaling in response to WNT / NIK-->noncanonical NF-kB signaling / Ubiquitin-dependent degradation of Cyclin D / AUF1 (hnRNP D0) binds and destabilizes mRNA / activated TAK1 mediates p38 MAPK activation
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 / Caspase recruitment domain / Helicase/UvrB, N-terminal ...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 / Type III restriction enzyme, res subunit / Death-like domain superfamily / Helicase conserved C-terminal domain / : / Ubiquitin domain signature. / Ubiquitin conserved site / Ubiquitin domain / Ubiquitin family / Ubiquitin homologues / helicase superfamily c-terminal domain / Ubiquitin domain profile. / Ubiquitin-like 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 / Ubiquitin-like domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Polyubiquitin-B / Interferon-induced helicase C domain-containing protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsSong B / Chen Y
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)81971538 China
CitationJournal: Immunity / Year: 2021
Title: Ordered assembly of the cytosolic RNA-sensing MDA5-MAVS signaling complex via binding to unanchored K63-linked poly-ubiquitin chains.
Authors: Bin Song / Yun Chen / Xin Liu / Fei Yuan / Eddie Yong Jun Tan / Yixuan Lei / Ning Song / Yinqi Han / Bruce D Pascal / Patrick R Griffin / Cheng Luo / Bin Wu / Dahai Luo / Jie Zheng /
Abstract: The RNA sensor MDA5 recruits the signaling adaptor MAVS to initiate type I interferon signaling and downstream antiviral responses, a process that requires K63-linked polyubiquitin chains. Here, we ...The RNA sensor MDA5 recruits the signaling adaptor MAVS to initiate type I interferon signaling and downstream antiviral responses, a process that requires K63-linked polyubiquitin chains. Here, we examined the mechanisms whereby K63-polyUb chain regulate MDA5 activation. Only long unanchored K63-polyUb (n ≥ 8) could mediate tetramerization of the caspase activation and recruitment domains of MDA5 (CARDs). Cryoelectron microscopy structures of a polyUb-bound CARDs tetramer and a polyUb-bound CARDs-CARD assembly revealed a tower-like formation, wherein eight Ubs tethered along the outer rim of the helical shell, bridging CARDs and CARD tetramers into proximity. ATP binding and hydrolysis promoted the stabilization of RNA-bound MDA5 prior to MAVS activation via allosteric effects on CARDs-polyUb complex. Abundant ATP prevented basal activation of apo MDA5. Our findings reveal the ordered assembly of a MDA5 signaling complex competent to recruit and activate MAVS and highlight differences with RIG-I in terms of CARD orientation and Ub sensing that suggest different abilities to induce antiviral responses.
History
DepositionDec 9, 2020-
Header (metadata) releaseOct 13, 2021-
Map releaseOct 13, 2021-
UpdateMay 29, 2024-
Current statusMay 29, 2024Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.513
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.513
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7dnj
  • Surface level: 0.513
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_30785.png

Downloads & links

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Map

FileDownload / File: emd_30785.map.gz / Format: CCP4 / Size: 38.4 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.05 Å/pix.
x 216 pix.
= 225.72 Å		1.05 Å/pix.
x 216 pix.
= 225.72 Å		1.05 Å/pix.
x 216 pix.
= 225.72 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.045 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.513 / Movie #1: 0.513
Minimum - Maximum-1.0914057 - 2.1761625
Average (Standard dev.)0.0033250267 (±0.08097556)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions216216216
Spacing216216216
CellA=B=C: 225.71999 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0451.0451.045
M x/y/z216216216
origin x/y/z0.0000.0000.000
length x/y/z225.720225.720225.720
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS216216216
D min/max/mean-1.0912.1760.003

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Supplemental data

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Sample components

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Entire : k63polyUb bound MDA5 CARDs complex

EntireName: k63polyUb bound MDA5 CARDs complex
Components
  • Complex: k63polyUb bound MDA5 CARDs complex
    • Complex: k63polyUb
      • Protein or peptide: Interferon-induced helicase C domain-containing protein 1
      • Protein or peptide: Ubiquitin
    • Complex: MDA5 CARDs

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Supramolecule #1: k63polyUb bound MDA5 CARDs complex

SupramoleculeName: k63polyUb bound MDA5 CARDs complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #2: k63polyUb

SupramoleculeName: k63polyUb / type: complex / ID: 2 / Parent: 1 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: MDA5 CARDs

SupramoleculeName: MDA5 CARDs / type: complex / ID: 3 / Parent: 1 / Macromolecule list: all

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

MacromoleculeName: Interferon-induced helicase C domain-containing protein 1
type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO / EC number: RNA helicase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.825883 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MSNGYSTDEN FRYLISCFRA RVKMYIQVEP VLDYLTFLPA EVKEQIQRTV ATSGNMQAVE LLLSTLEKGV WHLGWTREFV EALRRTGSP LAARYMNPEL TDLPSPSFEN AHDEYLQLLN LLQPTLVDKL LVRDVLDKCM EEELLTIEDR NRIAAAENNG N ESGVRELL ...String:
MSNGYSTDEN FRYLISCFRA RVKMYIQVEP VLDYLTFLPA EVKEQIQRTV ATSGNMQAVE LLLSTLEKGV WHLGWTREFV EALRRTGSP LAARYMNPEL TDLPSPSFEN AHDEYLQLLN LLQPTLVDKL LVRDVLDKCM EEELLTIEDR NRIAAAENNG N ESGVRELL KRIVQKENWF SAFLNVLRQT GNNELVQELT GSDCSESNAE

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

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Macromolecule #2: Ubiquitin

MacromoleculeName: Ubiquitin / type: protein_or_peptide / ID: 2 / Number of copies: 8 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 8.576831 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MQIFVKTLTG KTITLEVEPS DTIENVKAKI QDKEGIPPDQ QRLIFAGKQL EDGRTLSDYN IQKESTLHLV LRLRGG

UniProtKB: Polyubiquitin-B

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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

Concentration0.8 mg/mL
BufferpH: 7.5
VitrificationCryogen name: OTHER

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 70.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 143814
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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