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- EMDB-22367: Human DPP9-CARD8 complex -

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Basic information

Entry
Database: EMDB / ID: EMD-22367
TitleHuman DPP9-CARD8 complex
Map data
Sample
  • Complex: DPP9-CARD8 complex
    • Protein or peptide: Dipeptidyl peptidase 9
    • Protein or peptide: Caspase recruitment domain-containing protein 8
KeywordsCARD8 / DPP9 / inflammasome / Val-boroPro (VbP) / talabostat / innate immunity / IMMUNE SYSTEM / HYDROLASE
Function / homology
Function and homology information


CARD8 inflammasome complex assembly / NACHT domain binding / Formation of apoptosome / cysteine-type endopeptidase activator activity / inhibition of cysteine-type endopeptidase activity / negative regulation of NLRP3 inflammasome complex assembly / NLRP3 inflammasome complex / dipeptidyl-peptidase IV / CARD domain binding / negative regulation of lipopolysaccharide-mediated signaling pathway ...CARD8 inflammasome complex assembly / NACHT domain binding / Formation of apoptosome / cysteine-type endopeptidase activator activity / inhibition of cysteine-type endopeptidase activity / negative regulation of NLRP3 inflammasome complex assembly / NLRP3 inflammasome complex / dipeptidyl-peptidase IV / CARD domain binding / negative regulation of lipopolysaccharide-mediated signaling pathway / self proteolysis / dipeptidyl-peptidase activity / Regulation of the apoptosome activity / negative regulation of programmed cell death / Hydrolases; Acting on peptide bonds (peptidases) / regulation of canonical NF-kappaB signal transduction / pattern recognition receptor activity / negative regulation of interleukin-1 beta production / negative regulation of NF-kappaB transcription factor activity / pyroptotic inflammatory response / cell leading edge / cysteine-type endopeptidase activator activity involved in apoptotic process / antiviral innate immune response / positive regulation of cysteine-type endopeptidase activity involved in apoptotic process / negative regulation of tumor necrosis factor-mediated signaling pathway / negative regulation of canonical NF-kappaB signal transduction / aminopeptidase activity / serine-type peptidase activity / molecular condensate scaffold activity / positive regulation of interleukin-1 beta production / peptidase activity / regulation of apoptotic process / defense response to virus / microtubule / protein homodimerization activity / protein-containing complex / proteolysis / nucleoplasm / identical protein binding / nucleus / cytosol / cytoplasm
Similarity search - Function
FIIND domain / Function to find / FIIND domain profile. / Dipeptidyl peptidase 8 /9 ,N-terminal / Dipeptidyl peptidase 8 and 9 N-terminal / Dipeptidylpeptidase IV, N-terminal domain / Dipeptidyl peptidase IV (DPP IV) N-terminal region / CARD domain / CARD caspase recruitment domain profile. / Caspase recruitment domain ...FIIND domain / Function to find / FIIND domain profile. / Dipeptidyl peptidase 8 /9 ,N-terminal / Dipeptidyl peptidase 8 and 9 N-terminal / 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
Similarity search - Domain/homology
Dipeptidyl peptidase 9 / Caspase recruitment domain-containing protein 8
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsSharif H / Hollingsworth LR
Funding support United States, 1 items
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
DepositionJul 28, 2020-
Header (metadata) releaseMay 26, 2021-
Map releaseMay 26, 2021-
UpdateMar 6, 2024-
Current statusMar 6, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.005
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.005
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7jkq
  • Surface level: 0.007
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_22367.png

Downloads & links

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Map

FileDownload / File: emd_22367.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.825 Å
Density
Contour LevelBy AUTHOR: 0.003 / Movie #1: 0.005
Minimum - Maximum-0.042496335 - 0.06656379
Average (Standard dev.)0.000025673238 (±0.001095574)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 330.0 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.8250.8250.825
M x/y/z400400400
origin x/y/z0.0000.0000.000
length x/y/z330.000330.000330.000
α/β/γ90.00090.00090.000
start NX/NY/NZ727265
NX/NY/NZ157157169
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS400400400
D min/max/mean-0.0420.0670.000

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Supplemental data

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Sample components

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Entire : DPP9-CARD8 complex

EntireName: DPP9-CARD8 complex
Components
  • Complex: DPP9-CARD8 complex
    • Protein or peptide: Dipeptidyl peptidase 9
    • Protein or peptide: Caspase recruitment domain-containing protein 8

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Supramolecule #1: DPP9-CARD8 complex

SupramoleculeName: DPP9-CARD8 complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Dipeptidyl peptidase 9

MacromoleculeName: Dipeptidyl peptidase 9 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: dipeptidyl-peptidase IV
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 98.38432 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MATTGTPTAD RGDAAATDDP AARFQVQKHS WDGLRSIIHG SRKYSGLIVN KAPHDFQFVQ KTDESGPHSH RLYYLGMPYG SRENSLLYS EIPKKVRKEA LLLLSWKQML DHFQATPHHG VYSREEELLR ERKRLGVFGI TSYDFHSESG LFLFQASNSL F HCRDGGKN ...String:
MATTGTPTAD RGDAAATDDP AARFQVQKHS WDGLRSIIHG SRKYSGLIVN KAPHDFQFVQ KTDESGPHSH RLYYLGMPYG SRENSLLYS EIPKKVRKEA LLLLSWKQML DHFQATPHHG VYSREEELLR ERKRLGVFGI TSYDFHSESG LFLFQASNSL F HCRDGGKN GFMVSPMKPL EIKTQCSGPR MDPKICPADP AFFSFINNSD LWVANIETGE ERRLTFCHQG LSNVLDDPKS AG VATFVIQ EEFDRFTGYW WCPTASWEGS EGLKTLRILY EEVDESEVEV IHVPSPALEE RKTDSYRYPR TGSKNPKIAL KLA EFQTDS QGKIVSTQEK ELVQPFSSLF PKVEYIARAG WTRDGKYAWA MFLDRPQQWL QLVLLPPALF IPSTENEEQR LASA RAVPR NVQPYVVYEE VTNVWINVHD IFYPFPQSEG EDELCFLRAN ECKTGFCHLY KVTAVLKSQG YDWSEPFSPG EDEFK CPIK EEIALTSGEW EVLARHGSKI WVNEETKLVY FQGTKDTPLE HHLYVVSYEA AGEIVRLTTP GFSHSCSMSQ NFDMFV SHY SSVSTPPCVH VYKLSGPDDD PLHKQPRFWA SMMEAASCPP DYVPPEIFHF HTRSDVRLYG MIYKPHALQP GKKHPTV LF VYGGPQVQLV NNSFKGIKYL RLNTLASLGY AVVVIDGRGS CQRGLRFEGA LKNQMGQVEI EDQVEGLQFV AEKYGFID L SRVAIHGWSY GGFLSLMGLI HKPQVFKVAI AGAPVTVWMA YDTGYTERYM DVPENNQHGY EAGSVALHVE KLPNEPNRL LILHGFLDEN VHFFHTNFLV SQLIRAGKPY QLQIYPNERH SIRCPESGEH YEVTLLHFLQ EYL

UniProtKB: Dipeptidyl peptidase 9

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Macromolecule #2: Caspase recruitment domain-containing protein 8

MacromoleculeName: Caspase recruitment domain-containing protein 8 / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 60.716875 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MEKKECPEKS SSSEEELPRR DSGSSRNIDA SKLIRLQGSR KLLVDNSIRE LQYTKTGIFF QAEACVTNDT VYRELPCVSE TLCDISHFF QEDDETEAEP LLFRAVPECQ LSGGDIPSVS EEQESSEGQD SGDICSEENQ IVSSYASKVC FEIEEDYKNR Q FLGPEGNV ...String:
MEKKECPEKS SSSEEELPRR DSGSSRNIDA SKLIRLQGSR KLLVDNSIRE LQYTKTGIFF QAEACVTNDT VYRELPCVSE TLCDISHFF QEDDETEAEP LLFRAVPECQ LSGGDIPSVS EEQESSEGQD SGDICSEENQ IVSSYASKVC FEIEEDYKNR Q FLGPEGNV DVELIDKSTN RYSVWFPTAG WYLWSATGLG FLVRDEVTVT IAFGSWSQHL ALDLQHHEQW LVGGPLFDVT AE PEEAVAE IHLPHFISLQ AGEVDVSWFL VAHFKNEGMV LEHPARVEPF YAVLESPSFS LMGILLRIAS GTRLSIPITS NTL IYYHPH PEDIKFHLYL VPSDALLTKA IDDEEDRFHG VRLQTSPPME PLNFGSSYIV SNSANLKVMP KELKLSYRSP GEIQ HFSKF YAGQMKEPIQ LEITEKRHGT LVWDTEVKPV DLQLVAASAP PPFSGAAFVK ENHRQLQARM GDLKGVLDDL QDNEV LTEN EKELVEQEKT RQSKNEALLS MVEKKGDLAL DVLFRSISER DPYLVSYLRQ QNL

UniProtKB: Caspase recruitment domain-containing protein 8

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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

Concentration0.5 mg/mL
BufferpH: 7.5 / Details: 25mM HEPES, pH 7.5, 150 mM NaCl, 1 mM TCEP
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 30 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 278 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: OTHER
Electron opticsCalibrated magnification: 10500 / Illumination mode: SPOT SCAN / Imaging mode: OTHER / Cs: 2.7 mm / Nominal defocus max: 2.2 µm / Nominal defocus min: -0.8 µm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recording#0 - Image recording ID: 1 / #0 - Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / #0 - Number grids imaged: 4 / #0 - Number real images: 3306 / #0 - Average exposure time: 2.22 sec. / #0 - Average electron dose: 58.5 e/Å2 / #0 - Details: stage tilt 0 degrees / #1 - Image recording ID: 2 / #1 - Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / #1 - Number grids imaged: 4 / #1 - Number real images: 2488 / #1 - Average exposure time: 2.25 sec. / #1 - Average electron dose: 64.99 e/Å2 / #1 - Details: stage tilt 37 degrees
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 3.1)
Final 3D classificationNumber classes: 5 / Avg.num./class: 50000 / Software - Name: RELION (ver. 3.1)
Final angle assignmentType: ANGULAR RECONSTITUTION / Software - Name: RELION (ver. 3.1)
Final reconstructionNumber classes used: 1 / Applied symmetry - Point group: C1 (asymmetric) / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.1) / Number images used: 120998
Image recording ID1
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

6eoq


Chain - Chain ID: A / Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementProtocol: OTHER
Output model

PDB-7jkq:
Human DPP9-CARD8 complex

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