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- EMDB-32484: Human NLRP1 complexed with thioredoxin -

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Basic information

Entry
Database: EMDB / ID: EMD-32484
TitleHuman NLRP1 complexed with thioredoxin
Map dataB-factor sharpened map
Sample
  • Complex: hNLRP1 complexed with sfTRX
    • Complex: hNLRP1
      • Protein or peptide: NACHT, LRR and PYD domains-containing protein 1, N-terminus
    • Complex: sfTRX
      • Protein or peptide: Thioredoxin
  • Ligand: PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER
  • Ligand: MAGNESIUM ION
KeywordsNLRP1 / inflammasome / thioredoxin / IMMUNE SYSTEM
Function / homology
Function and homology information


NLRP1 inflammasome complex assembly / cysteine-type endopeptidase activator activity / NLRP1 inflammasome complex / canonical inflammasome complex / The NLRP1 inflammasome / self proteolysis / Hydrolases; Acting on peptide bonds (peptidases) / stress-activated protein kinase signaling cascade / pattern recognition receptor activity / pattern recognition receptor signaling pathway ...NLRP1 inflammasome complex assembly / cysteine-type endopeptidase activator activity / NLRP1 inflammasome complex / canonical inflammasome complex / The NLRP1 inflammasome / self proteolysis / Hydrolases; Acting on peptide bonds (peptidases) / stress-activated protein kinase signaling cascade / pattern recognition receptor activity / pattern recognition receptor signaling pathway / cellular response to UV-B / pyroptotic inflammatory response / cysteine-type endopeptidase activator activity involved in apoptotic process / antiviral innate immune response / response to muramyl dipeptide / protein-disulfide reductase activity / signaling adaptor activity / positive regulation of interleukin-1 beta production / molecular condensate scaffold activity / Hydrolases; Acting on acid anhydrides; Acting on acid anhydrides to facilitate cellular and subcellular movement / protein homooligomerization / positive regulation of inflammatory response / activation of cysteine-type endopeptidase activity involved in apoptotic process / : / double-stranded RNA binding / peptidase activity / regulation of inflammatory response / double-stranded DNA binding / regulation of apoptotic process / neuron apoptotic process / defense response to virus / defense response to bacterium / protein domain specific binding / apoptotic process / nucleolus / enzyme binding / ATP hydrolysis activity / nucleoplasm / ATP binding / nucleus / cytosol / cytoplasm
Similarity search - Function
FIIND domain / Function to find / FIIND domain profile. / CARD8/ASC/NALP1, CARD domain / NACHT, LRR and PYD domains-containing protein, helical domain HD2 / NLRC4 helical domain HD2 / NOD2, winged helix domain / NOD2 winged helix domain / DAPIN domain / DAPIN domain profile. ...FIIND domain / Function to find / FIIND domain profile. / CARD8/ASC/NALP1, CARD domain / NACHT, LRR and PYD domains-containing protein, helical domain HD2 / NLRC4 helical domain HD2 / NOD2, winged helix domain / NOD2 winged helix domain / DAPIN domain / DAPIN domain profile. / PAAD/DAPIN/Pyrin domain / NACHT nucleoside triphosphatase / NACHT domain / NACHT-NTPase domain profile. / PAAD/DAPIN/Pyrin domain / Leucine rich repeat, ribonuclease inhibitor type / Leucine Rich repeat / Thioredoxin / Leucine Rich Repeat / CARD domain / CARD caspase recruitment domain profile. / Caspase recruitment domain / Thioredoxin / Leucine-rich repeat profile. / Death-like domain superfamily / Thioredoxin domain profile. / Thioredoxin domain / Leucine-rich repeat / Leucine-rich repeat domain superfamily / Thioredoxin-like superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Thioredoxin / NACHT, LRR and PYD domains-containing protein 1
Similarity search - Component
Biological speciesHomo sapiens (human) / Spodoptera frugiperda (fall armyworm)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsZhang Z / Ohto U
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nature / Year: 2023
Title: Structural basis for thioredoxin-mediated suppression of NLRP1 inflammasome.
Authors: Zhikuan Zhang / Takuma Shibata / Akiko Fujimura / Jiro Kitaura / Kensuke Miyake / Umeharu Ohto / Toshiyuki Shimizu /
Abstract: Inflammasome sensors detect pathogen- and danger-associated molecular patterns and promote inflammation and pyroptosis. NLRP1 was the first inflammasome sensor to be described, and its ...Inflammasome sensors detect pathogen- and danger-associated molecular patterns and promote inflammation and pyroptosis. NLRP1 was the first inflammasome sensor to be described, and its hyperactivation is linked to autoinflammatory disease and cancer. However, the mechanism underlying the activation and regulation of NLRP1 has not been clearly elucidated. Here we identify ubiquitously expressed endogenous thioredoxin (TRX) as a binder of NLRP1 and a suppressor of the NLRP1 inflammasome. The cryo-electron microscopy structure of human NLRP1 shows NLRP1 bound to Spodoptera frugiperda TRX. Mutagenesis studies of NLRP1 and human TRX show that TRX in the oxidized form binds to the nucleotide-binding domain subdomain of NLRP1. This observation highlights the crucial role of redox-active cysteines of TRX in NLRP1 binding. Cellular assays reveal that TRX suppresses NLRP1 inflammasome activation and thus negatively regulates NLRP1. Our data identify the TRX system as an intrinsic checkpoint for innate immunity and provide opportunities for future therapeutic intervention in NLRP1 inflammasome activation targeting this system.
History
DepositionDec 28, 2021-
Header (metadata) releaseJul 5, 2023-
Map releaseJul 5, 2023-
UpdateOct 18, 2023-
Current statusOct 18, 2023Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_32484.png

Downloads & links

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Map

FileDownload / File: emd_32484.map.gz / Format: CCP4 / Size: 15.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationB-factor sharpened map
Voxel sizeX=Y=Z: 1.245 Å
Density
Contour LevelBy AUTHOR: 0.04
Minimum - Maximum-0.20341289 - 0.3748638
Average (Standard dev.)0.0002691291 (±0.007625023)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions160160160
Spacing160160160
CellA=B=C: 199.2 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: Unsharpened map

Fileemd_32484_additional_1.map
AnnotationUnsharpened map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: DeepEMhancer sharpened map

Fileemd_32484_additional_2.map
AnnotationDeepEMhancer sharpened map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : hNLRP1 complexed with sfTRX

EntireName: hNLRP1 complexed with sfTRX
Components
  • Complex: hNLRP1 complexed with sfTRX
    • Complex: hNLRP1
      • Protein or peptide: NACHT, LRR and PYD domains-containing protein 1, N-terminus
    • Complex: sfTRX
      • Protein or peptide: Thioredoxin
  • Ligand: PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER
  • Ligand: MAGNESIUM ION

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Supramolecule #1: hNLRP1 complexed with sfTRX

SupramoleculeName: hNLRP1 complexed with sfTRX / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #2: hNLRP1

SupramoleculeName: hNLRP1 / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Spodoptera frugiperda (fall armyworm)

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Supramolecule #3: sfTRX

SupramoleculeName: sfTRX / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2

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Macromolecule #1: NACHT, LRR and PYD domains-containing protein 1, N-terminus

MacromoleculeName: NACHT, LRR and PYD domains-containing protein 1, N-terminus
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 101.999953 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: SFPYSPSEPH LGSPSQPTST AVLMPWIHEL PAGCTQGSER RVLRQLPDTS GRRWREISAS LLYQALPSSP DHESPSQESP NAPTSTAVL GSWGSPPQPS LAPREQEAPG TQWPLDETSG IYYTEIRERE REKSEKGRPP WAAVVGTPPQ AHTSLQPHHH P WEPSVRES ...String:
SFPYSPSEPH LGSPSQPTST AVLMPWIHEL PAGCTQGSER RVLRQLPDTS GRRWREISAS LLYQALPSSP DHESPSQESP NAPTSTAVL GSWGSPPQPS LAPREQEAPG TQWPLDETSG IYYTEIRERE REKSEKGRPP WAAVVGTPPQ AHTSLQPHHH P WEPSVRES LCSTWPWKNE DFNQKFTQLL LLQRPHPRSQ DPLVKRSWPD YVEENRGHLI EIRDLFGPGL DTQEPRIVIL QG AAGIGKS TLARQVKEAW GRGQLYGDRF QHVFYFSCRE LAQSKVVSLA ELIGKDGTAT PAPIRQILSR PERLLFILDG VDE PGWVLQ EPSSELCLHW SQPQPADALL GSLLGKTILP EASFLITART TALQNLIPSL EQARWVEVLG FSESSRKEYF YRYF TDERQ AIRAFRLVKS NKELWALCLV PWVSWLACTC LMQQMKRKEK LTLTSKTTTT LCLHYLAQAL QAQPLGPQLR DLCSL AAEG IWQKKTLFSP DDLRKHGLDG AIISTFLKMG ILQEHPIPLS YSFIHLCFQE FFAAMSYVLE DEKGRGKHSN CIIDLE KTL EAYGIHGLFG ASTTRFLLGL LSDEGEREME NIFHCRLSQG RNLMQWVPSL QLLLQPHSLE SLHCLYETRN KTFLTQV MA HFEEMGMCVE TDMELLVCTF CIKFSRHVKK LQLIEGRQHR STWSPTMVVL FRWVPVTDAY WQILFSVLKV TRNLKELD L SGNSLSHSAV KSLCKTLRRP RCLLETLRLA GCGLTAEDCK DLAFGLRANQ TLTELDLSFN VLTDAGAKHL CQRLRQPSC KLQRLQLVSC GLTSDCCQDL ASVLSASPSL KELDLQQNNL DDVGVRLLCE GLRHPACKLI RLGLDQTTLS DEMRQELRAL EQEKPQLLI FSRRKPSVMT P

UniProtKB: NACHT, LRR and PYD domains-containing protein 1

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Macromolecule #2: Thioredoxin

MacromoleculeName: Thioredoxin / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Spodoptera frugiperda (fall armyworm)
Molecular weightTheoretical: 11.94489 KDa
SequenceString:
MSIHIKDSDD LKNRLAEAGD KLVVIDFMAT WCGPCKMIGP KLDEMANEMS DCIVVLKVDV DECEDIATEY NINSMPTFVF VKNSKKIEE FSGANVDKLR NTIIKLK

UniProtKB: Thioredoxin

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Macromolecule #3: PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER

MacromoleculeName: PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER / type: ligand / ID: 3 / Number of copies: 1 / Formula: AGS
Molecular weightTheoretical: 523.247 Da
Chemical component information

ChemComp-AGS:
PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER / ATP-gamma-S, energy-carrying molecule analogue*YM

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Macromolecule #4: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 4 / 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 stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.2 µm / Nominal defocus min: 1.2 µm
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 63.2 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE / Details: Ab initio reconstruction
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 72304

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