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- EMDB-30458: Cryo-EM structure of rNLRP1-rDPP9 complex -

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Basic information

Entry
Database: EMDB / ID: EMD-30458
TitleCryo-EM structure of rNLRP1-rDPP9 complex
Map data
Sample
  • Complex: Complex of Nlrp1-FIIND with DPP9 dimer
    • Protein or peptide: Dipeptidyl peptidase 9
    • Protein or peptide: NLR family protein 1
KeywordsIMMUNE SYSTEM
Function / homology
Function and homology information


negative regulation of cellular defense response / NLRP1 inflammasome complex assembly / NLRP1 inflammasome complex / canonical inflammasome complex / cysteine-type endopeptidase activator activity / programmed necrotic cell death / dipeptidyl-peptidase IV / positive regulation of pyroptotic inflammatory response / self proteolysis / dipeptidyl-peptidase activity ...negative regulation of cellular defense response / NLRP1 inflammasome complex assembly / NLRP1 inflammasome complex / canonical inflammasome complex / cysteine-type endopeptidase activator activity / programmed necrotic cell death / dipeptidyl-peptidase IV / positive regulation of pyroptotic inflammatory response / self proteolysis / dipeptidyl-peptidase activity / negative regulation of programmed cell death / Hydrolases; Acting on peptide bonds (peptidases) / pattern recognition receptor activity / cellular response to UV-B / pyroptotic inflammatory response / cell leading edge / response to muramyl dipeptide / signaling adaptor activity / antiviral innate immune response / serine-type peptidase activity / positive regulation of interleukin-1 beta production / molecular condensate scaffold activity / protein homooligomerization / positive regulation of inflammatory response / double-stranded RNA binding / peptidase activity / regulation of inflammatory response / double-stranded DNA binding / scaffold protein binding / defense response to virus / regulation of apoptotic process / neuron apoptotic process / microtubule / defense response to bacterium / protein domain specific binding / neuronal cell body / enzyme binding / signal transduction / ATP hydrolysis activity / protein-containing complex / proteolysis / ATP binding / identical protein binding / nucleus / cytosol
Similarity search - Function
FIIND domain / Function to find / FIIND domain profile. / CARD8/ASC/NALP1, CARD domain / Dipeptidyl peptidase 8 /9 ,N-terminal / Dipeptidyl peptidase 8 and 9 N-terminal / : / NACHT, LRR and PYD domains-containing protein, helical domain HD2 / NLRC4 helical domain HD2 / NOD2, winged helix domain ...FIIND domain / Function to find / FIIND domain profile. / CARD8/ASC/NALP1, CARD domain / Dipeptidyl peptidase 8 /9 ,N-terminal / Dipeptidyl peptidase 8 and 9 N-terminal / : / NACHT, LRR and PYD domains-containing protein, helical domain HD2 / NLRC4 helical domain HD2 / NOD2, winged helix domain / NOD2 winged helix domain / NACHT nucleoside triphosphatase / NACHT domain / NACHT-NTPase domain profile. / Leucine rich repeat, ribonuclease inhibitor type / : / Dipeptidylpeptidase IV, N-terminal domain / Dipeptidyl peptidase IV (DPP IV) N-terminal region / CARD domain / CARD caspase recruitment domain profile. / Caspase recruitment domain / Leucine Rich repeat / Peptidase S9, prolyl oligopeptidase, catalytic domain / Prolyl oligopeptidase family / Death-like domain superfamily / Leucine-rich repeat / Leucine-rich repeat domain superfamily / Alpha/Beta hydrolase fold / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
NACHT, LRR and PYD domains-containing protein 1 allele 2 / dipeptidyl-peptidase IV
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.18 Å
AuthorsHuang MH / Zhang XX
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)31421001 to J.C. China
CitationJournal: Nature / Year: 2021
Title: Structural and biochemical mechanisms of NLRP1 inhibition by DPP9.
Authors: Menghang Huang / Xiaoxiao Zhang / Gee Ann Toh / Qin Gong / Jia Wang / Zhifu Han / Bin Wu / Franklin Zhong / Jijie Chai /
Abstract: Nucleotide-binding domain, leucine-rich repeat receptors (NLRs) mediate innate immunity by forming inflammasomes. Activation of the NLR protein NLRP1 requires autocleavage within its function-to-find ...Nucleotide-binding domain, leucine-rich repeat receptors (NLRs) mediate innate immunity by forming inflammasomes. Activation of the NLR protein NLRP1 requires autocleavage within its function-to-find domain (FIIND). In resting cells, the dipeptidyl peptidases DPP8 and DPP9 interact with the FIIND of NLRP1 and suppress spontaneous NLRP1 activation; however, the mechanisms through which this occurs remain unknown. Here we present structural and biochemical evidence that full-length rat NLRP1 (rNLRP1) and rat DPP9 (rDPP9) form a 2:1 complex that contains an autoinhibited rNLRP1 molecule and an active UPA-CARD fragment of rNLRP1. The ZU5 domain is required not only for autoinhibition of rNLRP1 but also for assembly of the 2:1 complex. Formation of the complex prevents UPA-mediated higher-order oligomerization of UPA-CARD fragments and strengthens ZU5-mediated NLRP1 autoinhibition. Structure-guided biochemical and functional assays show that both NLRP1 binding and enzymatic activity are required for DPP9 to suppress NLRP1 in human cells. Together, our data reveal the mechanism of DPP9-mediated inhibition of NLRP1 and shed light on the activation of the NLRP1 inflammasome.
History
DepositionAug 14, 2020-
Header (metadata) releaseMar 24, 2021-
Map releaseMar 24, 2021-
UpdateMar 27, 2024-
Current statusMar 27, 2024Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.015
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.015
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7crw
  • Surface level: 0.015
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_30458.png

Downloads & links

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Map

FileDownload / File: emd_30458.map.gz / Format: CCP4 / Size: 52.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.06 Å/pix.
x 240 pix.
= 254.64 Å		1.06 Å/pix.
x 240 pix.
= 254.64 Å		1.06 Å/pix.
x 240 pix.
= 254.64 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.061 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.015 / Movie #1: 0.015
Minimum - Maximum-0.03259771 - 0.070418745
Average (Standard dev.)0.0002718619 (±0.0024192687)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions240240240
Spacing240240240
CellA=B=C: 254.64 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0611.0611.061
M x/y/z240240240
origin x/y/z0.0000.0000.000
length x/y/z254.640254.640254.640
α/β/γ90.00090.00090.000
start NX/NY/NZ1219875
NX/NY/NZ141223232
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS240240240
D min/max/mean-0.0330.0700.000

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Supplemental data

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Sample components

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Entire : Complex of Nlrp1-FIIND with DPP9 dimer

EntireName: Complex of Nlrp1-FIIND with DPP9 dimer
Components
  • Complex: Complex of Nlrp1-FIIND with DPP9 dimer
    • Protein or peptide: Dipeptidyl peptidase 9
    • Protein or peptide: NLR family protein 1

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Supramolecule #1: Complex of Nlrp1-FIIND with DPP9 dimer

SupramoleculeName: Complex of Nlrp1-FIIND with DPP9 dimer / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Rattus norvegicus (Norway rat)

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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
Source (natural)Organism: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 98.203273 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MSGGVSPVEQ VAAGDMDDTA ARFCVQKHSW DGLRNIIHGS RKSSGLIVSK APHDFQFVQK PDESGPHSHR LYYLGMPYGS RENSLLYSE IPKKVRKEAL LLLSWKQMLD HFQATPHHGV YSREEELLRE RKRLGVFGIT SYDFHSESGL FLFQASNSLF H CRDGGKNG ...String:
MSGGVSPVEQ VAAGDMDDTA ARFCVQKHSW DGLRNIIHGS RKSSGLIVSK APHDFQFVQK PDESGPHSHR LYYLGMPYGS RENSLLYSE IPKKVRKEAL LLLSWKQMLD HFQATPHHGV YSREEELLRE RKRLGVFGIT SYDFHSESGL FLFQASNSLF H CRDGGKNG FMVSPMKPLE IKTQCSGPRM DPKICPADPA FFSFINNNDL WVANIETGEE RRLTFCHQGS ASVLDNPKSA GV ATFVIQE EFDRFTGCWW CPTASWEGSG GLKTLRILYE EVDESEVEVI HVPSPALEER KTDSYRYPRT GSKNPKIALK LAE LQTDHQ GKIVSSCEKE LVQPFSSLFP KVEYIARAGW TRDGRYAWAM FLDRPQQRLQ LVLLPPALFI PTLESEAQWQ EAAR AIPKN VQPFIIYEEV TNVWINVHDI FHPFPQAEGQ QDFCFLRANE CKTGFCHLYR VTVDLKTNDY DWTEPLSPAE DEFKC PIKE EVALTSGEWE VLSRHGSKIW VNEQTKLVYF QGTKDTPLEH HLYVVSYESA GEIVRLTTPG FSHSCSMSQN FDMFVS HYS SVSTPPCVHV YKLSGPDDDP LHKQPRFWAS MMEAASCPPD YVPPEIFHFH TRADVQLYGM IYKPHTLQPG RKHPTVL FV YGGPQVQLVN NSFKGIKYLR LNTLASLGYA VVVIDGRGSC QRGLHFEGAL KNQMGQVEIE DQVEGLQYVA EKYGFIDL S RVAIHGWSYG GFLSLMGLIH KPQVFKVAIA GAPVTVWMAY DTGYTERYMD VPENNQQGYE AGSVALHVEK LPNEPNRLL ILHGFLDENV HFFHTNFLVS QLIRAGKPYQ LQIYPNERHS IRCRESGEHY EVTLLHFLQE HL

UniProtKB: dipeptidyl-peptidase IV

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Macromolecule #2: NLR family protein 1

MacromoleculeName: NLR family protein 1 / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 138.577859 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MEESQSKQES NTRVAQHGSQ QDVDPTFQTK RALEKERSKP RPRPLPRVQL QSLPGWSSTS KDVPLSQLIR EMDHESRRCI HRSKKKLDR SEHISQGTIP EIYEKRKETI SHTQSMEQKY LFQNFTKLLL LQKCCPGGSE KLVRESWHPC VPEEGGHMIE I QDLFDPNL ...String:
MEESQSKQES NTRVAQHGSQ QDVDPTFQTK RALEKERSKP RPRPLPRVQL QSLPGWSSTS KDVPLSQLIR EMDHESRRCI HRSKKKLDR SEHISQGTIP EIYEKRKETI SHTQSMEQKY LFQNFTKLLL LQKCCPGGSE KLVRESWHPC VPEEGGHMIE I QDLFDPNL DTEKKPQLVI IEGAAGIGKS TLARQVKRAW DEGQLYRDRF QHVFFFSCRE LAQCKQLSLA ELIAQGQEVP TA PTRQILS RPEKLLFILD GIDEPAWVLE DQNPELCVHW SQAQPVHTLL GSLLGKSILP EASLMLTART TALQKLVPSL GQP HRVEVL GFSEFERKDY FYKYFAKERN TIIDFNLIGS IPVLLTLCEV PWVCWLLCTC LEKQMQQGEV LSLTSQTTTA LCLK YLSLT IPGQHLSTQL RTLCSLAAEG ICQRRTLFSK SDLCKQGLAE DAIATFLKIG VLQRQPSSLS YSFAHLCLQE FFAAM SYIL EDSEEAHGDM GNDRTVETLV ERYGRQNLFE APTVRFLLGL LNTREMREME NIFACKFPWE TKLKLLQSII GEPFCQ PCH LGLFHCLYEN QEEELLTETM LCFPLTASGP NHMEATVFQT NVKRLVIQTD MELMVVTFCI TFSHVRSLRL KGKGQQE YK LTAPAMVLYR WTPISEASWK VLFSNLKCTR NLEELDLSGN PLSYSAVRSL CTALRQPGCR LKTLWLVDCG LTSRCCSF L ASMLSAHSRL AELDLRLNDL GDNGVRQLCE GLRNPACNLS ILRLDQASLS EQVITELRAL ETKNPKLFIS STWMSHMTM PTENTDGEES LTSSKQQQQQ SGDKHMEPLG TDDDFWGPSG PVSTEVVDRE RNLYRVRLPM AGSYHCPSTG LHFVVTRAVT IEIGFCAWS QFLHETPLQH SHMVAGPLFD IKAEHGAVTA VCLPHFVSLQ EGKVDSSLFH VAHFQDHGMV LETPARVEPH F AVLENPSF SPMGVLLRMI PAVGHFIPIT SITLIYYRLY LEDITFHLYL VPNDCTIRKA IDEEELKFQF VRINKPPPVD AL YVGSRYI VSSSKEVEIL PKELELCYRS PRESQLFSEI YVGNIGSGIN LQLTDKKYMN LIWEALLKPG DLRPALPRMA SAP KDAPAL LHFVDQHREQ LVARVTSVDP LLDKLHGLVL SEEDYETVRA EATNQDKMRK LFRGSRSWSW DCKDHFYQAL KETH PHLIM DLLEKSGGVS VRL

UniProtKB: NACHT, LRR and PYD domains-containing protein 1 allele 2

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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: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.18 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 182116
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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