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- PDB-7jn7: Human DPP9-CARD8 complex -

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Basic information

Entry
Database: PDB / ID: 7jn7
TitleHuman DPP9-CARD8 complex
Components
  • Caspase recruitment domain-containing protein 8
  • Dipeptidyl peptidase 9
KeywordsIMMUNE SYSTEM / HYDROLASE / CARD8 / DPP9 / inflammasome / Val-boroPro (VbP) / talabostat / innate immunity
Function / homology
Function and homology information


CARD8 inflammasome complex assembly / CARD8 inflammasome complex / NACHT domain binding / Formation of apoptosome / CARD domain binding / NLRP3 inflammasome complex / self proteolysis / dipeptidyl-peptidase IV / negative regulation of NLRP3 inflammasome complex assembly / cysteine-type endopeptidase activator activity ...CARD8 inflammasome complex assembly / CARD8 inflammasome complex / NACHT domain binding / Formation of apoptosome / CARD domain binding / NLRP3 inflammasome complex / self proteolysis / dipeptidyl-peptidase IV / negative regulation of NLRP3 inflammasome complex assembly / cysteine-type endopeptidase activator activity / negative regulation of lipopolysaccharide-mediated signaling pathway / Regulation of the apoptosome activity / dipeptidyl-peptidase activity / Hydrolases; Acting on peptide bonds (peptidases) / negative regulation of programmed cell death / negative regulation of interleukin-1 beta production / pattern recognition receptor activity / pyroptotic inflammatory response / cell leading edge / negative regulation of tumor necrosis factor-mediated signaling pathway / aminopeptidase activity / negative regulation of canonical NF-kappaB signal transduction / antiviral innate immune response / serine-type peptidase activity / intrinsic apoptotic signaling pathway / activation of innate immune response / positive regulation of interleukin-1 beta production / molecular condensate scaffold activity / peptidase activity / regulation of apoptotic process / defense response to virus / microtubule / inflammatory response / protein homodimerization activity / protein-containing complex / proteolysis / nucleoplasm / identical protein binding / nucleus / cytoplasm / cytosol
Similarity search - Function
FIIND domain / Function to find / UPA-FIIND domain / FIIND domain profile. / Dipeptidyl peptidase 8 /9 ,N-terminal / Dipeptidyl peptidase 8 and 9 N-terminal / : / Dipeptidylpeptidase IV, N-terminal domain / 8 Propeller / Methanol Dehydrogenase; Chain A ...FIIND domain / Function to find / UPA-FIIND domain / FIIND domain profile. / Dipeptidyl peptidase 8 /9 ,N-terminal / Dipeptidyl peptidase 8 and 9 N-terminal / : / Dipeptidylpeptidase IV, N-terminal domain / 8 Propeller / Methanol Dehydrogenase; Chain A / : / Dipeptidylpeptidase IV, N-terminal domain / Dipeptidyl peptidase IV (DPP IV) N-terminal region / CARD domain / CARD caspase recruitment domain profile. / Caspase recruitment domain / Peptidase S9, prolyl oligopeptidase, catalytic domain / Prolyl oligopeptidase family / Death-like domain superfamily / Alpha/Beta hydrolase fold / Mainly Beta
Similarity search - Domain/homology
Chem-GK2 / Dipeptidyl peptidase 9 / Caspase recruitment domain-containing protein 8
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsSharif, H. / Hollingsworth, L.R.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)R01 Al124491 United States
CitationJournal: Immunity / Year: 2021
Title: Dipeptidyl peptidase 9 sets a threshold for CARD8 inflammasome formation by sequestering its active C-terminal fragment.
Authors: Humayun Sharif / L Robert Hollingsworth / Andrew R Griswold / Jeffrey C Hsiao / Qinghui Wang / Daniel A Bachovchin / Hao Wu /
Abstract: CARD8 detects intracellular danger signals and forms a caspase-1 activating inflammasome. Like the related inflammasome sensor NLRP1, CARD8 autoprocesses into noncovalently associated N-terminal (NT) ...CARD8 detects intracellular danger signals and forms a caspase-1 activating inflammasome. Like the related inflammasome sensor NLRP1, CARD8 autoprocesses into noncovalently associated N-terminal (NT) and C-terminal (CT) fragments and binds the cellular dipeptidyl peptidases DPP8 and 9 (DPP8/9). Certain danger-associated signals, including the DPP8/9 inhibitor Val-boroPro (VbP) and HIV protease, induce proteasome-mediated NT degradation and thereby liberate the inflammasome-forming CT. Here, we report cryoelectron microscopy (cryo-EM) structures of CARD8 bound to DPP9, revealing a repressive ternary complex consisting of DPP9, full-length CARD8, and CARD8-CT. Unlike NLRP1-CT, CARD8-CT does not interact with the DPP8/9 active site and is not directly displaced by VbP. However, larger DPP8/9 active-site probes can directly weaken this complex in vitro, and VbP itself nevertheless appears to disrupt this complex, perhaps indirectly, in cells. Thus, DPP8/9 inhibitors can activate the CARD8 inflammasome by promoting CARD8 NT degradation and by weakening ternary complex stability.
History
DepositionAug 4, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 19, 2021Provider: repository / Type: Initial release
Revision 1.1Jun 9, 2021Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Jul 28, 2021Group: Database references / Category: citation / Item: _citation.journal_volume / _citation.page_first
Revision 1.3Oct 23, 2024Group: Data collection / Database references ...Data collection / Database references / Refinement description / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / em_3d_fitting_list / em_admin / pdbx_entry_details / pdbx_initial_refinement_model / pdbx_modification_feature
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _em_3d_fitting_list.accession_code / _em_3d_fitting_list.initial_refinement_model_id / _em_3d_fitting_list.source_name / _em_3d_fitting_list.type / _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

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  • Deposited structure unit
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Structure viewerMolecule:
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Assembly

Deposited unit
A: Dipeptidyl peptidase 9
B: Caspase recruitment domain-containing protein 8
C: Caspase recruitment domain-containing protein 8
D: Dipeptidyl peptidase 9
hetero molecules


Theoretical massNumber of molelcules
Total (without water)325,3866
Polymers324,9584
Non-polymers4282
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area8220 Å2
ΔGint-35 kcal/mol
Surface area79950 Å2

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Components

#1: Protein Dipeptidyl peptidase 9 / DP9 / Dipeptidyl peptidase IV-related protein 2 / DPRP-2 / Dipeptidyl peptidase IX / DPP IX / ...DP9 / Dipeptidyl peptidase IV-related protein 2 / DPRP-2 / Dipeptidyl peptidase IX / DPP IX / Dipeptidyl peptidase-like protein 9 / DPLP9


Mass: 101761.984 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DPP9, DPRP2 / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: Q86TI2, dipeptidyl-peptidase IV
#2: Protein Caspase recruitment domain-containing protein 8 / Apoptotic protein NDPP1 / CARD-inhibitor of NF-kappa-B-activating ligand / CARDINAL / DACAR / Tumor ...Apoptotic protein NDPP1 / CARD-inhibitor of NF-kappa-B-activating ligand / CARDINAL / DACAR / Tumor up-regulated CARD-containing antagonist of CASP9 / TUCAN / CARD8


Mass: 60716.875 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CARD8, KIAA0955, NDPP1 / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: Q9Y2G2
#3: Chemical ChemComp-GK2 / [(2~{R})-1-[(2~{R})-2-azanyl-3-methyl-butanoyl]pyrrolidin-2-yl]boronic acid


Mass: 214.070 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C9H19BN2O3 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
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: DPP9-CARD8 complex / Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human) / Cell: HEK293 / Plasmid: pcDNA3.1
Buffer solutionpH: 7.5 / Details: 25 mM HEPES, pH 7.5, 150 mM NaCl, 1 mM TCEP
SpecimenConc.: 0.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 278 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: OTHER / Accelerating voltage: 300 kV / Illumination mode: SPOT SCAN
Electron lensMode: OTHER / Calibrated magnification: 10500 X / Nominal defocus max: 2200 nm / Nominal defocus min: -800 nm / Cs: 2.7 mm
Specimen holderSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recording

Imaging-ID: 1 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Num. of grids imaged: 4

IDAverage exposure time (sec.)Electron dose (e/Å2)Num. of real imagesDetails
12.2258.53306stage tilt 0 degrees
22.2564.992488stage tilt 37 degrees

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Processing

SoftwareName: PHENIX / Version: 1.18.2_3874: / Classification: refinement
EM software
IDNameVersionCategory
1crYOLO1.5particle selection
2SerialEM3.7image acquisition
4CTFFIND9.03CTF correction
7PHENIX1.18.1model fitting
9PHENIX1.18.1model refinement
10RELION3.1initial Euler assignment
11RELION3.1final Euler assignment
12RELION3.1classification
13RELION3.13D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 1404573 / Details: no tilt dataset
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 205538 / Algorithm: FOURIER SPACE / Num. of class averages: 1 / Symmetry type: POINT
Atomic model buildingProtocol: OTHER
Atomic model buildingPDB-ID: 6EOQ

6eoq


Pdb chain-ID: A / Accession code: 6EOQ / Source name: PDB / Type: experimental model
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00917315
ELECTRON MICROSCOPYf_angle_d1.32123530
ELECTRON MICROSCOPYf_dihedral_angle_d8.9582273
ELECTRON MICROSCOPYf_chiral_restr0.0772479
ELECTRON MICROSCOPYf_plane_restr0.0113056

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