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- PDB-7c76: Cryo-EM structure of human TLR3 in complex with UNC93B1 -

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Basic information

Entry
Database: PDB / ID: 7c76
TitleCryo-EM structure of human TLR3 in complex with UNC93B1
Components
  • Protein unc-93 homolog B1
  • Toll-like receptor 3
KeywordsIMMUNE SYSTEM / Toll-like receptors / UNC93B1 / MFS
Function / homology
Function and homology information


type III interferon production / TLR3 deficiency - HSE / UNC93B1 deficiency - HSE / positive regulation of type III interferon production / TICAM1 deficiency - HSE / response to dsRNA / TRAF3 deficiency - HSE / toll-like receptor 7 signaling pathway / T cell antigen processing and presentation / regulation of dendritic cell cytokine production ...type III interferon production / TLR3 deficiency - HSE / UNC93B1 deficiency - HSE / positive regulation of type III interferon production / TICAM1 deficiency - HSE / response to dsRNA / TRAF3 deficiency - HSE / toll-like receptor 7 signaling pathway / T cell antigen processing and presentation / regulation of dendritic cell cytokine production / Toll Like Receptor 3 (TLR3) Cascade / Toll-like receptor binding / TLR3-mediated TICAM1-dependent programmed cell death / inflammatory response to wounding / toll-like receptor 3 signaling pathway / detection of virus / activation of NF-kappaB-inducing kinase activity / toll-like receptor 9 signaling pathway / necroptotic signaling pathway / RIP-mediated NFkB activation via ZBP1 / early phagosome / endolysosome membrane / Trafficking and processing of endosomal TLR / positive regulation of cytokine production involved in inflammatory response / hyperosmotic response / positive regulation of macrophage cytokine production / toll-like receptor signaling pathway / cellular response to exogenous dsRNA / pattern recognition receptor activity / RSV-host interactions / negative regulation of osteoclast differentiation / response to exogenous dsRNA / positive regulation of interferon-alpha production / ubiquitin-like protein ligase binding / cellular response to interferon-beta / JNK cascade / extrinsic apoptotic signaling pathway / positive regulation of chemokine production / positive regulation of interleukin-12 production / positive regulation of interferon-beta production / Regulation of TBK1, IKKε-mediated activation of IRF3, IRF7 upon TLR3 ligation / TICAM1,TRAF6-dependent induction of TAK1 complex / TICAM1-dependent activation of IRF3/IRF7 / TICAM1, RIP1-mediated IKK complex recruitment / positive regulation of interleukin-8 production / cellular response to mechanical stimulus / microglial cell activation / intracellular protein transport / cellular response to virus / positive regulation of interleukin-6 production / positive regulation of JNK cascade / cellular response to type II interferon / male gonad development / cellular response to xenobiotic stimulus / antigen processing and presentation of exogenous peptide antigen via MHC class II / positive regulation of type II interferon production / cell morphogenesis / positive regulation of angiogenesis / positive regulation of tumor necrosis factor production / positive regulation of inflammatory response / transmembrane signaling receptor activity / double-stranded RNA binding / signaling receptor activity / defense response to virus / early endosome / positive regulation of canonical NF-kappaB signal transduction / lysosome / endosome / endosome membrane / defense response to bacterium / positive regulation of apoptotic process / Golgi membrane / innate immune response / lysosomal membrane / positive regulation of gene expression / endoplasmic reticulum membrane / endoplasmic reticulum / signal transduction / positive regulation of transcription by RNA polymerase II / membrane / identical protein binding / plasma membrane / cytoplasm
Similarity search - Function
Ion channel regulatory protein UNC-93 / Protein unc-93 homolog B1 / Toll-like receptor 3 trans-membrane domain / Toll-like receptor 3 trans-membrane domain / TIR domain / Leucine Rich repeat / Cysteine-rich flanking region, C-terminal / Leucine rich repeat C-terminal domain / Toll - interleukin 1 - resistance / TIR domain profile. ...Ion channel regulatory protein UNC-93 / Protein unc-93 homolog B1 / Toll-like receptor 3 trans-membrane domain / Toll-like receptor 3 trans-membrane domain / TIR domain / Leucine Rich repeat / Cysteine-rich flanking region, C-terminal / Leucine rich repeat C-terminal domain / Toll - interleukin 1 - resistance / TIR domain profile. / Leucine-rich repeat, SDS22-like subfamily / Toll/interleukin-1 receptor homology (TIR) domain / Toll/interleukin-1 receptor homology (TIR) domain superfamily / Leucine rich repeat / Leucine-rich repeat, typical subtype / Leucine-rich repeats, typical (most populated) subfamily / Leucine-rich repeat profile. / Leucine-rich repeat / Leucine-rich repeat domain superfamily
Similarity search - Domain/homology
Toll-like receptor 3 / Protein unc-93 homolog B1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsOhto, U. / Ishida, H. / Shimizu, T.
CitationJournal: Nat Struct Mol Biol / Year: 2021
Title: Cryo-EM structures of Toll-like receptors in complex with UNC93B1.
Authors: Hanako Ishida / Jinta Asami / Zhikuan Zhang / Tomohiro Nishizawa / Hideki Shigematsu / Umeharu Ohto / Toshiyuki Shimizu /
Abstract: Nucleic acid-sensing Toll-like receptors (TLRs) play a pivotal role in innate immunity by recognizing foreign DNA and RNA. Compartmentalization of these TLRs in the endosome limits their activation ...Nucleic acid-sensing Toll-like receptors (TLRs) play a pivotal role in innate immunity by recognizing foreign DNA and RNA. Compartmentalization of these TLRs in the endosome limits their activation by self-derived nucleic acids and reduces the possibility of autoimmune reactions. Although chaperone Unc-93 homolog B1, TLR signaling regulator (UNC93B1) is indispensable for the trafficking of TLRs from the endoplasmic reticulum to the endosome, mechanisms of UNC93B1-mediated TLR regulation remain largely unknown. Here, we report two cryo-EM structures of human and mouse TLR3-UNC93B1 complexes and a human TLR7-UNC93B1 complex. UNC93B1 exhibits structural similarity to the major facilitator superfamily transporters. Both TLRs interact with the UNC93B1 amino-terminal six-helix bundle through their transmembrane and luminal juxtamembrane regions, but the complexes of TLR3 and TLR7 with UNC93B1 differ in their oligomerization state. The structural information provided here should aid in designing compounds to combat autoimmune diseases.
History
DepositionMay 23, 2020Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jan 6, 2021Provider: repository / Type: Initial release
Revision 1.1Jan 27, 2021Group: Database references / Category: citation / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Feb 24, 2021Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Oct 23, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

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Assembly

Deposited unit
A: Toll-like receptor 3
B: Protein unc-93 homolog B1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)175,92818
Polymers170,6422
Non-polymers5,28616
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Toll-like receptor 3


Mass: 103946.320 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TLR3 / Cell line (production host): Expi293F / Production host: Homo sapiens (human) / References: UniProt: O15455
#2: Protein Protein unc-93 homolog B1 / hUNC93B1


Mass: 66695.969 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: UNC93B1, UNC93, UNC93B / Cell line (production host): Expi293F / Production host: Homo sapiens (human) / References: UniProt: Q9H1C4
#3: Polysaccharide
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 5
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}}LINUCSPDB-CARE
#4: Polysaccharide beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta- ...beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 586.542 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/2,3,2/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5]/1-1-2/a4-b1_b4-c1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{}}}}LINUCSPDB-CARE
#5: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 9
Source method: isolated from a genetically manipulated source
Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
Has ligand of interestN
Has protein modificationY

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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: Complex of TLR3 and UNC93B1 / Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human) / Cell: Expi293F
Buffer solutionpH: 5.5
Details: 25 mM Hepes-NaOH, pH 7.5, 0.2 M NaCl, and 0.01% GDN
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
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: OTHER
Electron lensMode: BRIGHT FIELD
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: NONE
3D reconstructionResolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 134000 / Symmetry type: POINT

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