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- PDB-5uzb: Cryo-EM structure of the MAL TIR domain filament -

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Basic information

Entry
Database: PDB / ID: 5uzb
TitleCryo-EM structure of the MAL TIR domain filament
ComponentsToll/interleukin-1 receptor domain-containing adapter protein
KeywordsIMMUNE SYSTEM / TIR domain / adaptor proteins / TLR signaling / homotypic protein interactions
Function / homology
Function and homology information


positive regulation of interleukin-15 production / TIRAP-dependent toll-like receptor 4 signaling pathway / regulation of interferon-beta production / cellular response to bacterial lipopeptide / positive regulation of toll-like receptor 3 signaling pathway / Toll-like receptor 4 binding / positive regulation of toll-like receptor 2 signaling pathway / Toll-like receptor 2 binding / positive regulation of toll-like receptor 4 signaling pathway / positive regulation of chemokine (C-X-C motif) ligand 1 production ...positive regulation of interleukin-15 production / TIRAP-dependent toll-like receptor 4 signaling pathway / regulation of interferon-beta production / cellular response to bacterial lipopeptide / positive regulation of toll-like receptor 3 signaling pathway / Toll-like receptor 4 binding / positive regulation of toll-like receptor 2 signaling pathway / Toll-like receptor 2 binding / positive regulation of toll-like receptor 4 signaling pathway / positive regulation of chemokine (C-X-C motif) ligand 1 production / myeloid cell differentiation / positive regulation of chemokine (C-X-C motif) ligand 2 production / MyD88 deficiency (TLR2/4) / positive regulation of neutrophil chemotaxis / MyD88-dependent toll-like receptor signaling pathway / IRAK4 deficiency (TLR2/4) / regulation of innate immune response / MyD88:MAL(TIRAP) cascade initiated on plasma membrane / toll-like receptor 4 signaling pathway / 3'-UTR-mediated mRNA stabilization / regulation of stress-activated MAPK cascade / cellular response to lipoteichoic acid / endocytic vesicle / canonical NF-kappaB signal transduction / signaling adaptor activity / positive regulation of B cell proliferation / phosphatidylinositol-4,5-bisphosphate binding / extrinsic component of cytoplasmic side of plasma membrane / positive regulation of interleukin-12 production / protein kinase C binding / positive regulation of interleukin-8 production / positive regulation of protein-containing complex assembly / positive regulation of JNK cascade / ruffle membrane / positive regulation of interleukin-6 production / protein-macromolecule adaptor activity / positive regulation of tumor necrosis factor production / positive regulation of NF-kappaB transcription factor activity / ER-Phagosome pathway / positive regulation of canonical NF-kappaB signal transduction / response to lipopolysaccharide / positive regulation of ERK1 and ERK2 cascade / cell surface receptor signaling pathway / molecular adaptor activity / defense response to Gram-positive bacterium / inflammatory response / innate immune response / cell surface / identical protein binding / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Toll-interleukin 1 receptor domain-containing adaptor protein, Tirap / TIR domain / TIR domain profile. / Toll/interleukin-1 receptor homology (TIR) domain / Toll/interleukin-1 receptor homology (TIR) domain superfamily
Similarity search - Domain/homology
Toll/interleukin-1 receptor domain-containing adapter protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 7 Å
AuthorsVe, T. / Vajjhala, P.R. / Hedger, A. / Croll, T. / DiMaio, F. / Horsefield, S. / Yu, X. / Lavrencic, P. / Hassan, Z. / Morgan, G.P. ...Ve, T. / Vajjhala, P.R. / Hedger, A. / Croll, T. / DiMaio, F. / Horsefield, S. / Yu, X. / Lavrencic, P. / Hassan, Z. / Morgan, G.P. / Mansell, A. / Mobli, M. / O'Carrol, A. / Chauvin, B. / Gambin, Y. / Sierecki, E. / Landsberg, M.J. / Stacey, K.J. / Egelman, E.H. / Kobe, B.
Funding support Australia, 1items
OrganizationGrant numberCountry
National Health and Medical Research Council (NHMRC, Australia)1107804 Australia
CitationJournal: Nat Struct Mol Biol / Year: 2017
Title: Structural basis of TIR-domain-assembly formation in MAL- and MyD88-dependent TLR4 signaling.
Authors: Thomas Ve / Parimala R Vajjhala / Andrew Hedger / Tristan Croll / Frank DiMaio / Shane Horsefield / Xiong Yu / Peter Lavrencic / Zahid Hassan / Garry P Morgan / Ashley Mansell / Mehdi Mobli ...Authors: Thomas Ve / Parimala R Vajjhala / Andrew Hedger / Tristan Croll / Frank DiMaio / Shane Horsefield / Xiong Yu / Peter Lavrencic / Zahid Hassan / Garry P Morgan / Ashley Mansell / Mehdi Mobli / Ailis O'Carroll / Brieuc Chauvin / Yann Gambin / Emma Sierecki / Michael J Landsberg / Katryn J Stacey / Edward H Egelman / Bostjan Kobe /
Abstract: Toll-like receptor (TLR) signaling is a key innate immunity response to pathogens. Recruitment of signaling adapters such as MAL (TIRAP) and MyD88 to the TLRs requires Toll/interleukin-1 receptor ...Toll-like receptor (TLR) signaling is a key innate immunity response to pathogens. Recruitment of signaling adapters such as MAL (TIRAP) and MyD88 to the TLRs requires Toll/interleukin-1 receptor (TIR)-domain interactions, which remain structurally elusive. Here we show that MAL TIR domains spontaneously and reversibly form filaments in vitro. They also form cofilaments with TLR4 TIR domains and induce formation of MyD88 assemblies. A 7-Å-resolution cryo-EM structure reveals a stable MAL protofilament consisting of two parallel strands of TIR-domain subunits in a BB-loop-mediated head-to-tail arrangement. Interface residues that are important for the interaction are conserved among different TIR domains. Although large filaments of TLR4, MAL or MyD88 are unlikely to form during cellular signaling, structure-guided mutagenesis, combined with in vivo interaction assays, demonstrated that the MAL interactions defined within the filament represent a template for a conserved mode of TIR-domain interaction involved in both TLR and interleukin-1 receptor signaling.
History
DepositionFeb 25, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 26, 2017Provider: repository / Type: Initial release
Revision 1.1Aug 23, 2017Group: Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.pdbx_database_id_PubMed ..._citation.journal_abbrev / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 1.2Sep 20, 2017Group: Data collection / Database references / Category: citation / em_software
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _em_software.name
Revision 1.3Jul 18, 2018Group: Data collection / Category: em_software / Item: _em_software.name
Revision 1.4Jan 15, 2020Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization

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Structure visualization

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Assembly

Deposited unit
A: Toll/interleukin-1 receptor domain-containing adapter protein
B: Toll/interleukin-1 receptor domain-containing adapter protein
C: Toll/interleukin-1 receptor domain-containing adapter protein
D: Toll/interleukin-1 receptor domain-containing adapter protein
E: Toll/interleukin-1 receptor domain-containing adapter protein
F: Toll/interleukin-1 receptor domain-containing adapter protein
G: Toll/interleukin-1 receptor domain-containing adapter protein
H: Toll/interleukin-1 receptor domain-containing adapter protein
I: Toll/interleukin-1 receptor domain-containing adapter protein
J: Toll/interleukin-1 receptor domain-containing adapter protein
K: Toll/interleukin-1 receptor domain-containing adapter protein
L: Toll/interleukin-1 receptor domain-containing adapter protein
M: Toll/interleukin-1 receptor domain-containing adapter protein
N: Toll/interleukin-1 receptor domain-containing adapter protein


Theoretical massNumber of molelcules
Total (without water)275,64814
Polymers275,64814
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: assay for oligomerization
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
Toll/interleukin-1 receptor domain-containing adapter protein / TIR domain-containing adapter protein / Adaptor protein Wyatt / MyD88 adapter-like protein / MyD88-2


Mass: 19689.162 Da / Num. of mol.: 14 / Fragment: UNP residues 79-221
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TIRAP, MAL / Plasmid: pMCSG7 / Production host: Escherichia coli (E. coli) / References: UniProt: P58753

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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: MAL TIR domain filament / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
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
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen 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 FIELDBright-field microscopy
Specimen holderSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 20 e/Å2 / Film or detector model: FEI FALCON II (4k x 4k) / Num. of real images: 446

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Processing

EM software
IDNameCategory
1EMAN2particle selection
4CTFFIND3CTF correction
7UCSF Chimeramodel fitting
8Rosettamodel fitting
9iMDFFmodel fitting
14SPIDER3D reconstruction
15IHRSR3D reconstruction
16Rosettamodel refinement
17iMDFFmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: -26.8 ° / Axial rise/subunit: 15.5 Å / Axial symmetry: C6
3D reconstructionResolution: 7 Å / Resolution method: OTHER / Num. of particles: 17175 / Symmetry type: HELICAL

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