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- PDB-7dni: MDA5 CARDs-MAVS CARD polyUb complex -

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Basic information

Entry
Database: PDB / ID: 7dni
TitleMDA5 CARDs-MAVS CARD polyUb complex
Components
  • Interferon-induced helicase C domain-containing protein 1
  • Mitochondrial antiviral-signaling protein
  • Ubiquitin
KeywordsIMMUNE SYSTEM / Signaling / polyubiquitin
Function / homology
Function and homology information


positive regulation of IP-10 production / regulation of peroxisome organization / RIG-I binding / MDA-5 signaling pathway / regulation of type III interferon production / positive regulation of chemokine (C-C motif) ligand 5 production / positive regulation of myeloid dendritic cell cytokine production / CARD domain binding / detection of virus / NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10 ...positive regulation of IP-10 production / regulation of peroxisome organization / RIG-I binding / MDA-5 signaling pathway / regulation of type III interferon production / positive regulation of chemokine (C-C motif) ligand 5 production / positive regulation of myeloid dendritic cell cytokine production / CARD domain binding / detection of virus / NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10 / protein localization to mitochondrion / positive regulation of response to cytokine stimulus / positive regulation of type I interferon-mediated signaling pathway / hypothalamus gonadotrophin-releasing hormone neuron development / female meiosis I / peroxisomal membrane / positive regulation of protein monoubiquitination / mitochondrion transport along microtubule / fat pad development / pattern recognition receptor activity / TRAF6 mediated IRF7 activation / negative regulation of type I interferon-mediated signaling pathway / positive regulation of NLRP3 inflammasome complex assembly / cytoplasmic pattern recognition receptor signaling pathway / negative regulation of viral genome replication / type I interferon-mediated signaling pathway / female gonad development / seminiferous tubule development / cellular response to exogenous dsRNA / male meiosis I / positive regulation of intrinsic apoptotic signaling pathway by p53 class mediator / TRAF6 mediated NF-kB activation / antiviral innate immune response / protein sumoylation / positive regulation of type I interferon production / positive regulation of interferon-alpha production / ribonucleoprotein complex binding / energy homeostasis / regulation of neuron apoptotic process / signaling adaptor activity / regulation of proteasomal protein catabolic process / ubiquitin ligase complex / Maturation of protein E / Maturation of protein E / ER Quality Control Compartment (ERQC) / Myoclonic epilepsy of Lafora / FLT3 signaling by CBL mutants / Prevention of phagosomal-lysosomal fusion / positive regulation of defense response to virus by host / IRAK2 mediated activation of TAK1 complex / Alpha-protein kinase 1 signaling pathway / Glycogen synthesis / IRAK1 recruits IKK complex / IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation / Membrane binding and targetting of GAG proteins / Endosomal Sorting Complex Required For Transport (ESCRT) / IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation / PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1 / Negative regulation of FLT3 / Constitutive Signaling by NOTCH1 HD Domain Mutants / Regulation of FZD by ubiquitination / TICAM1,TRAF6-dependent induction of TAK1 complex / NOTCH2 Activation and Transmission of Signal to the Nucleus / TICAM1-dependent activation of IRF3/IRF7 / APC/C:Cdc20 mediated degradation of Cyclin B / p75NTR recruits signalling complexes / Downregulation of ERBB4 signaling / APC-Cdc20 mediated degradation of Nek2A / PINK1-PRKN Mediated Mitophagy / TRAF6-mediated induction of TAK1 complex within TLR4 complex / TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling / Pexophagy / activation of innate immune response / Regulation of innate immune responses to cytosolic DNA / InlA-mediated entry of Listeria monocytogenes into host cells / VLDLR internalisation and degradation / positive regulation of interferon-beta production / Downregulation of ERBB2:ERBB3 signaling / NF-kB is activated and signals survival / NRIF signals cell death from the nucleus / Regulation of PTEN localization / Activated NOTCH1 Transmits Signal to the Nucleus / Regulation of BACH1 activity / Translesion synthesis by REV1 / Synthesis of active ubiquitin: roles of E1 and E2 enzymes / Translesion synthesis by POLK / MAP3K8 (TPL2)-dependent MAPK1/3 activation / TICAM1, RIP1-mediated IKK complex recruitment / Downregulation of TGF-beta receptor signaling / Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE) / Translesion synthesis by POLI / Gap-filling DNA repair synthesis and ligation in GG-NER / Josephin domain DUBs / neuron projection morphogenesis / Regulation of activated PAK-2p34 by proteasome mediated degradation / InlB-mediated entry of Listeria monocytogenes into host cell / IKK complex recruitment mediated by RIP1 / JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 / TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) / regulation of mitochondrial membrane potential
Similarity search - Function
IPS1, CARD 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 ...IPS1, CARD 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 / 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 / Ubiquitin domain profile. / helicase superfamily c-terminal domain / 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 / Mitochondrial antiviral-signaling protein / Interferon-induced helicase C domain-containing protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / Resolution: 3.2 Å
AuthorsSong, B. / Chen, Y. / Luo, D.H. / Zheng, J.
Funding support China, 1items
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, 2020Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Oct 13, 2021Provider: repository / Type: Initial release
Revision 1.1Feb 16, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2May 29, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Assembly

Deposited unit
H: Ubiquitin
F: Ubiquitin
J: Ubiquitin
K: Ubiquitin
A: Interferon-induced helicase C domain-containing protein 1
B: Interferon-induced helicase C domain-containing protein 1
C: Interferon-induced helicase C domain-containing protein 1
D: Interferon-induced helicase C domain-containing protein 1
E: Ubiquitin
G: Ubiquitin
I: Ubiquitin
L: Ubiquitin
M: Mitochondrial antiviral-signaling protein
N: Mitochondrial antiviral-signaling protein
O: Mitochondrial antiviral-signaling protein
P: Mitochondrial antiviral-signaling protein


Theoretical massNumber of molelcules
Total (without water)209,28716
Polymers209,28716
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: mass spectrometry, HDX-MS
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area32920 Å2
ΔGint-79 kcal/mol
Surface area62720 Å2

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Components

#1: Protein
Ubiquitin


Mass: 8576.831 Da / Num. of mol.: 8
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: UBB / Production host: Escherichia coli (E. coli) / References: UniProt: P0CG47
#2: Protein
Interferon-induced helicase C domain-containing protein 1


Mass: 23825.883 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MDA5 / Production host: Escherichia coli (E. coli) / References: UniProt: Q9BYX4, RNA helicase
#3: Protein
Mitochondrial antiviral-signaling protein


Mass: 11342.082 Da / Num. of mol.: 4 / Mutation: D23K, E26K, E80K
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAVS / Production host: Escherichia coli (E. coli) / References: UniProt: Q7Z434

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: K63-polyUb bound MDA5CARDs-MAVSCARD complex / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.5
SpecimenConc.: 1.6 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: NO / Details: heterotetrameric complex

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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: OTHER
Electron lensMode: BRIGHT FIELD
Image recordingElectron dose: 70 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.18.2_3874: / Classification: refinement
CTF correctionType: NONE
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 212112 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00914312
ELECTRON MICROSCOPYf_angle_d0.74919395
ELECTRON MICROSCOPYf_dihedral_angle_d15.2251911
ELECTRON MICROSCOPYf_chiral_restr0.0492255
ELECTRON MICROSCOPYf_plane_restr0.0062497

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