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- PDB-6ncv: Cryo-EM structure of NLRP6 PYD filament -

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Basic information

Entry
Database: PDB / ID: 6ncv
TitleCryo-EM structure of NLRP6 PYD filament
ComponentsNACHT, LRR and PYD domains-containing protein 6
KeywordsSIGNALING PROTEIN / PROTEIN FIBRIL / death domain fold / helical assembly / inflammasome
Function / homology
Function and homology information


regulation of mucus secretion / NLRP6 inflammasome complex assembly / neutrophil-mediated killing of gram-positive bacterium / positive regulation of interleukin-18-mediated signaling pathway / NLRP6 inflammasome complex / lipoteichoic acid binding / host-mediated regulation of intestinal microbiota composition / vasopressin receptor activity / membraneless organelle / acute inflammatory response to antigenic stimulus ...regulation of mucus secretion / NLRP6 inflammasome complex assembly / neutrophil-mediated killing of gram-positive bacterium / positive regulation of interleukin-18-mediated signaling pathway / NLRP6 inflammasome complex / lipoteichoic acid binding / host-mediated regulation of intestinal microbiota composition / vasopressin receptor activity / membraneless organelle / acute inflammatory response to antigenic stimulus / canonical inflammasome complex / acute inflammatory response / negative regulation of toll-like receptor signaling pathway / pattern recognition receptor activity / pyroptotic inflammatory response / necroptotic process / negative regulation of type II interferon production / negative regulation of canonical NF-kappaB signal transduction / signaling adaptor activity / antiviral innate immune response / regulation of autophagy / negative regulation of inflammatory response to antigenic stimulus / molecular condensate scaffold activity / lipopolysaccharide binding / response to bacterium / peptide binding / wound healing / protein homooligomerization / negative regulation of ERK1 and ERK2 cascade / positive regulation of inflammatory response / double-stranded RNA binding / regulation of inflammatory response / defense response to virus / nuclear membrane / defense response to Gram-positive bacterium / ATP binding / plasma membrane / cytosol / cytoplasm
Similarity search - Function
: / NACHT, LRR and PYD domains-containing protein, helical domain HD2 / NLRC4 helical domain HD2 / NOD2, winged helix domain / NOD2 winged helix domain / Death Domain, Fas / Death Domain, Fas / DAPIN domain / DAPIN domain profile. / PAAD/DAPIN/Pyrin domain ...: / NACHT, LRR and PYD domains-containing protein, helical domain HD2 / NLRC4 helical domain HD2 / NOD2, winged helix domain / NOD2 winged helix domain / Death Domain, Fas / Death Domain, Fas / DAPIN domain / DAPIN domain profile. / PAAD/DAPIN/Pyrin domain / PAAD/DAPIN/Pyrin domain / NACHT nucleoside triphosphatase / NACHT domain / NACHT-NTPase domain profile. / Leucine rich repeat, ribonuclease inhibitor type / Death-like domain superfamily / Leucine-rich repeat domain superfamily / P-loop containing nucleoside triphosphate hydrolase / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
NACHT, LRR and PYD domains-containing protein 6
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 3.7 Å
AuthorsShen, C. / Fu, T.M. / Wu, H.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)Al124491 United States
National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health & Human Development (NIH/NICHD)HD087988 United States
CitationJournal: Proc Natl Acad Sci U S A / Year: 2019
Title: Molecular mechanism for NLRP6 inflammasome assembly and activation.
Authors: Chen Shen / Alvin Lu / Wen Jun Xie / Jianbin Ruan / Roberto Negro / Edward H Egelman / Tian-Min Fu / Hao Wu /
Abstract: Inflammasomes are large protein complexes that trigger host defense in cells by activating inflammatory caspases for cytokine maturation and pyroptosis. NLRP6 is a sensor protein in the nucleotide- ...Inflammasomes are large protein complexes that trigger host defense in cells by activating inflammatory caspases for cytokine maturation and pyroptosis. NLRP6 is a sensor protein in the nucleotide-binding domain (NBD) and leucine-rich repeat (LRR)-containing (NLR) inflammasome family that has been shown to play multiple roles in regulating inflammation and host defenses. Despite the significance of the NLRP6 inflammasome, little is known about the molecular mechanism behind its assembly and activation. Here we present cryo-EM and crystal structures of NLRP6 pyrin domain (PYD). We show that NLRP6 PYD alone is able to self-assemble into filamentous structures accompanied by large conformational changes and can recruit the ASC adaptor using PYD-PYD interactions. Using molecular dynamics simulations, we identify the surface that the NLRP6 PYD filament uses to recruit ASC PYD. We further find that full-length NLRP6 assembles in a concentration-dependent manner into wider filaments with a PYD core surrounded by the NBD and the LRR domain. These findings provide a structural understanding of inflammasome assembly by NLRP6 and other members of the NLR family.
History
DepositionDec 12, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 23, 2019Provider: repository / Type: Initial release
Revision 1.1Feb 6, 2019Group: Data collection / Database references / Category: citation
Item: _citation.journal_abbrev / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Feb 20, 2019Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Dec 11, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Mar 20, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Assembly

Deposited unit
A: NACHT, LRR and PYD domains-containing protein 6
B: NACHT, LRR and PYD domains-containing protein 6
C: NACHT, LRR and PYD domains-containing protein 6
D: NACHT, LRR and PYD domains-containing protein 6
E: NACHT, LRR and PYD domains-containing protein 6
F: NACHT, LRR and PYD domains-containing protein 6
G: NACHT, LRR and PYD domains-containing protein 6
H: NACHT, LRR and PYD domains-containing protein 6
I: NACHT, LRR and PYD domains-containing protein 6
J: NACHT, LRR and PYD domains-containing protein 6
K: NACHT, LRR and PYD domains-containing protein 6
L: NACHT, LRR and PYD domains-containing protein 6
M: NACHT, LRR and PYD domains-containing protein 6
N: NACHT, LRR and PYD domains-containing protein 6
O: NACHT, LRR and PYD domains-containing protein 6
P: NACHT, LRR and PYD domains-containing protein 6
Q: NACHT, LRR and PYD domains-containing protein 6
R: NACHT, LRR and PYD domains-containing protein 6
S: NACHT, LRR and PYD domains-containing protein 6
T: NACHT, LRR and PYD domains-containing protein 6
V: NACHT, LRR and PYD domains-containing protein 6


Theoretical massNumber of molelcules
Total (without water)250,56321
Polymers250,56321
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: microscopy, assay for oligomerization
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area35720 Å2
ΔGint26 kcal/mol
Surface area85000 Å2
SymmetryHelical symmetry: (Circular symmetry: 3 / Dyad axis: no / N subunits divisor: 1 / Num. of operations: 21 / Rise per n subunits: 13.8 Å / Rotation per n subunits: 56.8 °)

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Components

#1: Protein ...
NACHT, LRR and PYD domains-containing protein 6 / Angiotensin II/vasopressin receptor / PYRIN-containing APAF1-like protein 5 / NLRP6


Mass: 11931.579 Da / Num. of mol.: 21 / Fragment: PYD domain (UNP residues 1-106)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NLRP6, NALP6, PYPAF5 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P59044

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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: NLRP6 PYD / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.4
SpecimenConc.: 1.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportDetails: unspecified
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: FLOOD BEAM
Electron lensMode: BRIGHT FIELD
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: 56.8 ° / Axial rise/subunit: 13.8 Å / Axial symmetry: C3
3D reconstructionResolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 181477 / Symmetry type: HELICAL

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