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- EMDB-29496: Cryo-EM structure of full-length human NLRC4 inflammasome with C1... -

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Basic information

Entry
Database: EMDB / ID: EMD-29496
TitleCryo-EM structure of full-length human NLRC4 inflammasome with C11 symmetry
Map dataC1 map focused on three consecutive NLRC4 protomers
Sample
  • Complex: the complex of Needle, human NAIP and NLRC4
    • Protein or peptide: NLR family CARD domain-containing protein 4
KeywordsNLRC4 / NAIP / Inflammasome / IMMUNE SYSTEM
Function / homology
Function and homology information


IPAF inflammasome complex / The IPAF inflammasome / icosanoid biosynthetic process / canonical inflammasome complex / caspase binding / positive regulation of protein processing / activation of cysteine-type endopeptidase activity / pattern recognition receptor signaling pathway / TP53 Regulates Transcription of Caspase Activators and Caspases / pyroptosis ...IPAF inflammasome complex / The IPAF inflammasome / icosanoid biosynthetic process / canonical inflammasome complex / caspase binding / positive regulation of protein processing / activation of cysteine-type endopeptidase activity / pattern recognition receptor signaling pathway / TP53 Regulates Transcription of Caspase Activators and Caspases / pyroptosis / endopeptidase activator activity / detection of bacterium / activation of innate immune response / positive regulation of interleukin-1 beta production / protein homooligomerization / positive regulation of inflammatory response / activation of cysteine-type endopeptidase activity involved in apoptotic process / positive regulation of NF-kappaB transcription factor activity / defense response to bacterium / inflammatory response / positive regulation of apoptotic process / innate immune response / intracellular membrane-bounded organelle / apoptotic process / magnesium ion binding / protein homodimerization activity / ATP binding / identical protein binding / plasma membrane / cytosol / cytoplasm
Similarity search - Function
NLR family CARD domain-containing protein 4 / NLRC4, helical domain / NLRC4 helical domain / NACHT nucleoside triphosphatase / NACHT domain / NACHT-NTPase domain profile. / CARD domain / CARD caspase recruitment domain profile. / Caspase recruitment domain / Death-like domain superfamily ...NLR family CARD domain-containing protein 4 / NLRC4, helical domain / NLRC4 helical domain / NACHT nucleoside triphosphatase / NACHT domain / NACHT-NTPase domain profile. / CARD domain / CARD caspase recruitment domain profile. / Caspase recruitment domain / Death-like domain superfamily / Leucine-rich repeat domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
NLR family CARD domain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.8 Å
AuthorsMatico RE / Yu X / Miller R / Somani S / Ricketts MD / Kumar N / Steele RA / Medley Q / Berger S / Faustin B / Sharma S
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nat Struct Mol Biol / Year: 2024
Title: Structural basis of the human NAIP/NLRC4 inflammasome assembly and pathogen sensing.
Authors: Rosalie E Matico / Xiaodi Yu / Robyn Miller / Sandeep Somani / M Daniel Ricketts / Nikit Kumar / Ruth A Steele / Quintus Medley / Scott Berger / Benjamin Faustin / Sujata Sharma /
Abstract: The NLR family caspase activation and recruitment domain-containing 4 (NLRC4) inflammasome is a critical cytosolic innate immune machine formed upon the direct sensing of bacterial infection and in ...The NLR family caspase activation and recruitment domain-containing 4 (NLRC4) inflammasome is a critical cytosolic innate immune machine formed upon the direct sensing of bacterial infection and in response to cell stress during sterile chronic inflammation. Despite its major role in instigating the subsequent host immune response, a more complete understanding of the molecular events in the formation of the NLRC4 inflammasome in humans is lacking. Here we identify Bacillus thailandensis type III secretion system needle protein (Needle) as a potent trigger of the human NLR family apoptosis inhibitory protein (NAIP)/NLRC4 inflammasome complex formation and determine its structural features by cryogenic electron microscopy. We also provide a detailed understanding of how type III secretion system pathogen components are sensed by human NAIP to form a cascade of NLRC4 protomer through a critical lasso-like motif, a 'lock-key' activation model and large structural rearrangement, ultimately forming the full human NLRC4 inflammasome. These results shed light on key regulatory mechanisms specific to the NLRC4 inflammasome assembly, and the innate immune modalities of pathogen sensing in humans.
History
DepositionJan 20, 2023-
Header (metadata) releaseJan 3, 2024-
Map releaseJan 3, 2024-
UpdateJan 31, 2024-
Current statusJan 31, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_29496.png

Downloads & links

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Map

FileDownload / File: emd_29496.map.gz / Format: CCP4 / Size: 421.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationC1 map focused on three consecutive NLRC4 protomers
Voxel sizeX=Y=Z: 0.948 Å
Density
Contour LevelBy AUTHOR: 0.1
Minimum - Maximum-0.73938656 - 1.1010268
Average (Standard dev.)0.0010435247 (±0.01392409)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions480480480
Spacing480480480
CellA=B=C: 455.04 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: C11 map of full-length human NLRC4 inflammasome

Fileemd_29496_additional_1.map
AnnotationC11 map of full-length human NLRC4 inflammasome
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: C11 map of full-length human NLRC4 inflammasome

Fileemd_29496_additional_2.map
AnnotationC11 map of full-length human NLRC4 inflammasome
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: C11 map of full-length human NLRC4 inflammasome

Fileemd_29496_additional_3.map
AnnotationC11 map of full-length human NLRC4 inflammasome
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: C1 map focused on three consecutive NLRC4 protomers

Fileemd_29496_half_map_1.map
AnnotationC1 map focused on three consecutive NLRC4 protomers
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: C1 map focused on three consecutive NLRC4 protomers

Fileemd_29496_half_map_2.map
AnnotationC1 map focused on three consecutive NLRC4 protomers
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : the complex of Needle, human NAIP and NLRC4

EntireName: the complex of Needle, human NAIP and NLRC4
Components
  • Complex: the complex of Needle, human NAIP and NLRC4
    • Protein or peptide: NLR family CARD domain-containing protein 4

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Supramolecule #1: the complex of Needle, human NAIP and NLRC4

SupramoleculeName: the complex of Needle, human NAIP and NLRC4 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: NLR family CARD domain-containing protein 4

MacromoleculeName: NLR family CARD domain-containing protein 4 / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 117.027656 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: AEYCFNMNFI KDNSRALIQR MGMTVIKQIT DDLFVWNVLN REEVNIICCE KVEQDAARGI IHMILKKGSE SCNLFLKSLK EWNYPLFQD LNGQSLFHQT SEGDLDDLAQ DLKDLYHTPS FLNFYPLGED IDIIFNLKST FTEPVLWRKD QHHHRVEQLT L NGLLQALQ ...String:
AEYCFNMNFI KDNSRALIQR MGMTVIKQIT DDLFVWNVLN REEVNIICCE KVEQDAARGI IHMILKKGSE SCNLFLKSLK EWNYPLFQD LNGQSLFHQT SEGDLDDLAQ DLKDLYHTPS FLNFYPLGED IDIIFNLKST FTEPVLWRKD QHHHRVEQLT L NGLLQALQ SPCIIEGESG KGKSTLLQRI AMLWGSGKCK ALTKFKFVFF LRLSRAQGGL FETLCDQLLD IPGTIRKQTF MA MLLKLRQ RVLFLLDGYN EFKPQNCPEI EALIKENHRF KNMVIVTTTT ECLRHIRQFG ALTAEVGDMT EDSAQALIRE VLI KELAEG LLLQIQKSRC LRNLMKTPLF VVITCAIQMG ESEFHSHTQT TLFHTFYDLL IQKNKHKHKG VAASDFIRSL DHCG DLALE GVFSHKFDFE LQDVSSVNED VLLTTGLLCK YTAQRFKPKY KFFHKSFQEY TAGRRLSSLL TSHEPEEVTK GNGYL QKMV SISDITSTYS SLLRYTCGSS VEATRAVMKH LAAVYQHGCL LGLSIAKRPL WRQESLQSVK NTTEQEILKA ININSF VEC GIHLYQESTS KSALSQEFEA FFQGKSLYIN SGNIPDYLFD FFEHLPNCAS ALDFIKLDFY GGAMASWEKA AEDTGGI HM EEAPETYIPS RAVSLFFNWK QEFRTLEVTL RDFSKLNKQD IRYLGKIFSS ATSLRLQIKR CAGVAGSLSL VLSTCKNI Y SLMVEASPLT IEDERHITSV TNLKTLSIHD LQNQRLPGGL TDSLGNLKNL TKLIMDNIKM NEEDAIKLAE GLKNLKKMC LFHLTHLSDI GEGMDYIVKS LSSEPCDLEE IQLVSCCLSA NAVKILAQNL HNLVKLSILD LSENYLEKDG NEALHELIDR MNVLEQLTA LMLPWGCDVQ GSLSSLLKHL EEVPQLVKLG LKNWRLTDTE IRILGAFFGK NPLKNFQQLN LAGNRVSSDG W LAFMGVFE NLKQLVFFDF STKEFLPDPA LVRKLSQVLS KLTFLQEARL VGWQFDDDDL SVITGAFKLV TA

UniProtKB: NLR family CARD domain-containing protein 4

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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 GLACIOS
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.4 µm / Nominal defocus min: 1.2 µm
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 40.0 e/Å2

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Image processing

Startup modelType of model: INSILICO MODEL
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 72822

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