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Protein

NACHT, LRR and PYD domains-containing protein 3

Gene

Nlrp3

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

As the sensor component of the NLRP3 inflammasome, plays a crucial role in innate immunity and inflammation. In response to pathogens and other damage-associated signals, initiates the formation of the inflammasome polymeric complex, made of NLRP3, PYCARD and CASP1 (or possibly CASP4/CASP11). Recruitment of proCASP1 to the inflammasome promotes its activation and CASP1-catalyzed IL1B and IL18 maturation and secretion in the extracellular milieu. Activation of NLRP3 inflammasome is also required for HMGB1 secretion (PubMed:22801494). The active cytokines and HMGB1 stimulate inflammatory responses. Inflammasomes can also induce pyroptosis, an inflammatory form of programmed cell death. Under resting conditions, NLRP3 is autoinhibited. NLRP3 activation stimuli include extracellular ATP, reactive oxygen species, K+ efflux, crystals of monosodium urate or cholesterol, amyloid-beta fibers, environmental or industrial particles and nanoparticles, cytosolic dsRNA, etc. However, it is unclear what constitutes the direct NLRP3 activator. Activation in presence of cytosolic dsRNA is mediated by DHX33 (By similarity). Independently of inflammasome activation, regulates the differentiation of T helper 2 (Th2) cells and has a role in Th2 cell-dependent asthma and tumor growth. During Th2 differentiation, required for optimal IRF4 binding to IL4 promoter and for IRF4-dependent IL4 transcription. Binds to the consensus DNA sequence 5'-GRRGGNRGAG-3'. May also participate in the transcription of IL5, IL13, GATA3, CCR3, CCR4 and MAF (PubMed:26098997).By similarity6 Publications

Miscellaneous

Expression is increased in mice with experimental atopic dermatitis.

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi222 – 229ATPPROSITE-ProRule annotation8

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionActivator
Biological processImmunity, Inflammatory response, Innate immunity, Transcription, Transcription regulation
LigandATP-binding, Nucleotide-binding

Enzyme and pathway databases

ReactomeiR-MMU-5689901 Metalloprotease DUBs
R-MMU-844456 The NLRP3 inflammasome

Names & Taxonomyi

Protein namesi
Recommended name:
NACHT, LRR and PYD domains-containing protein 3
Alternative name(s):
Cold autoinflammatory syndrome 1 protein homolog
Cryopyrin
Mast cell maturation-associated-inducible protein 1
PYRIN-containing APAF1-like protein 1
Gene namesi
Name:Nlrp3
Synonyms:Cias1, Mmig1, Nalp3, Pypaf1
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 11

Organism-specific databases

MGIiMGI:2653833 Nlrp3

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm, Endoplasmic reticulum, Inflammasome, Nucleus, Secreted

Pathology & Biotechi

Disruption phenotypei

Knockout mice are fertile and appear healthy when housed in a standard specific pathogen-free environment. They do not exhibit any increase in serum IL1B after administration of R837 (an analog to guanosine and TLR7 agonist) and/or LPS (PubMed:16407890) (PubMed:16407888). When challenged with LPS, mutant mice are partially resistant to endotoxic shock (PubMed:16546100) (PubMed:16407890). Mutant mice display impaired contact hypersensitivity, a T-cell-mediated cellular immune response to repeated epicutaneous exposure to contact allergens, such as trinitrophenylchloride (PubMed:16546100). In a model of allergic asthma that promotes strictly Th2 responses, mutant animals show less infiltration of eosinophils and lymphocytes into the lungs than their wild-type counterparts, as well as less accumulation of mucus and lymphoid infiltrates. The concentration of Th2 cell-related cytokines, including IL-5 and IL-4, is also lower in lungs from mutant mice compared to wild-type (PubMed:26098997).4 Publications

Chemistry databases

ChEMBLiCHEMBL3779755

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000808871 – 1033NACHT, LRR and PYD domains-containing protein 3Add BLAST1033

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Disulfide bondi6 ↔ 104Redox-activeBy similarity

Post-translational modificationi

Ubiquitinated; undergoes both 'Lys-48'- and 'Lys-63'-linked polyubiquitination. Ubiquitination does not lead to degradation, but inhibits inflammasome activation (PubMed:23246432). Deubiquitination is catalyzed by BRCC3 and associated with NLRP3 activation and inflammasome assembly. This process can be induced by the activation of Toll-like receptors (by LPS), through a non-transcriptional pathway dependent on the mitochondrial production of reactive oxygen species, and by ATP.2 Publications
The disulfide bond in the pyrin domain might play a role in reactive oxygen species-mediated activation.By similarity

Keywords - PTMi

Disulfide bond, Ubl conjugation

Proteomic databases

PaxDbiQ8R4B8
PRIDEiQ8R4B8

PTM databases

iPTMnetiQ8R4B8
PhosphoSitePlusiQ8R4B8

Expressioni

Tissue specificityi

Expressed with high levels in peripheral blood leukocytes, including Th2 lymphocytes and macrophages (PubMed:15302403) (PubMed:26098997) (PubMed:16546100). Expressed at low levels in resting osteoblasts (at protein level) (PubMed:17907925).4 Publications

Developmental stagei

Up-regulated during CD4+ T-lymphocyte differentiation, in Th0, Th1 and Th2 cells. Not detected in naive CD4+ T-lymphocytes (at protein level).2 Publications

Inductioni

By activators of Toll-like receptors, such as lipoteichoic acid (LTA) (TLR2), polyinosine-polycytidylic acid (poly(I:C), a synthetic analog of dsRNA) (TLR3) and bacterial lipopolysaccharides (LPS) (TLR4) (PubMed:16546100). Up-regulated by IL2 via STAT5 signaling (PubMed:26098997). Slightly up-regulated in osteoblasts after exposure to invasive, but not invasion-defective, strains of Salmonella typhimurium (at protein level) (PubMed:17907925).3 Publications

Gene expression databases

BgeeiENSMUSG00000032691 Expressed in 62 organ(s), highest expression level in spinal cord
CleanExiMM_NLRP3
ExpressionAtlasiQ8R4B8 baseline and differential
GenevisibleiQ8R4B8 MM

Interactioni

Subunit structurei

Sensor component of NLRP3 inflammasomes. Inflammasomes are supramolecular complexes that assemble in the cytosol in response to pathogens and other damage-associated signals and play critical roles in innate immunity and inflammation. The core of NLRP3 inflammasomes consists of a signal sensor component (NLRP3), an adapter (ASC/PYCARD), which recruits an effector proinflammatory caspase (CASP1 and, possibly, CASP4 and CASP5). Within the complex, NLRP3 and PYCARD interact via their respective pyrin domains. This interaction initiates speck formation (nucleation) which greatly enhances further addition of soluble PYCARD molecules to the speck in a prion-like polymerization process. NLRP3 localizes at the end of each PYCARD filament. Clustered PYCARD nucleates the formation of CASP1 filaments through the interaction of their respective CARD domains, acting as a platform for CASP1 polymerization. CASP1 filament formation increases local enzyme concentration, resulting in trans-autocleavage and activation. Active CASP1 then processes IL1B and IL18 precursors, leading to the release of mature cytokines in the extracellular milieu and inflammatory response. Reconstituted ternary inflammasomes show star-shaped structures, in which multiple filaments, containing CASP1, protrude radially from a single central hub, containing the sensor protein and PYCARD. In this complex, the sensor protein is sub-stoichiometric to PYCARD, and PYCARD is further substoichiometric to CASP1, suggesting amplifications of signal transduction from the sensor, via the adapter, to the effector (By similarity). Interacts with MEFV; this interaction targets NLRP3 to degradation by autophagy, hence preventing excessive IL1B- and IL18-mediated inflammation (By similarity). Interacts with GBP5 (via DAPIN domain); this interaction promotes inflammasome assembly in response to microbial and soluble, but not crystalline, agents (By similarity). Interacts with EIF2AK2/PKR; this interaction requires EIF2AK2 activity, is accompanied by EIF2AK2 autophosphorylation and promotes inflammasome assembly in response to specific stimuli (PubMed:22801494). Interacts with PML (isoform PML-1) (via the LRR region); PML-mediated increase in NLRP3 inflammasome activation does not depend upon this interaction. Directly interacts with IRF4 (via LRR region); this interaction is required for optimal IRF4 binding to IL4 promoter and efficient IL4 transactivation during differentiation of Th2 helper T-cells (PubMed:26098997). Interacts (via NACHT domain) with DHX33 (via DEAH box) (By similarity).By similarity2 Publications

Binary interactionsi

GO - Molecular functioni

Protein-protein interaction databases

DIPiDIP-60132N
IntActiQ8R4B8, 5 interactors
STRINGi10090.ENSMUSP00000078440

Chemistry databases

BindingDBiQ8R4B8

Structurei

3D structure databases

ProteinModelPortaliQ8R4B8
SMRiQ8R4B8
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini1 – 91PyrinPROSITE-ProRule annotationAdd BLAST91
Domaini216 – 532NACHTPROSITE-ProRule annotationAdd BLAST317
Repeati739 – 759LRR 1Add BLAST21
Repeati768 – 789LRR 2Add BLAST22
Repeati796 – 816LRR 3Add BLAST21
Repeati825 – 846LRR 4Add BLAST22
Repeati853 – 873LRR 5Add BLAST21
Repeati882 – 903LRR 6Add BLAST22
Repeati910 – 930LRR 7Add BLAST21
Repeati939 – 960LRR 8Add BLAST22
Repeati967 – 988LRR 9Add BLAST22

Domaini

The LRR domain mediates the interaction with IRF4 and PML.By similarity1 Publication
Intramolecular interactions between NACHT and leucine-rich repeat (LRR) domains may be important for autoinhibition in the absence of activating signal.By similarity
The pyrin domain (also called DAPIN domain or PYD) is involved in PYCARD-binding.

Sequence similaritiesi

Belongs to the NLRP family.Curated

Keywords - Domaini

Leucine-rich repeat, Repeat

Phylogenomic databases

eggNOGiENOG410IE5X Eukaryota
ENOG4111H3D LUCA
GeneTreeiENSGT00900000140813
HOGENOMiHOG000294064
HOVERGENiHBG063656
InParanoidiQ8R4B8
KOiK12800
OMAiPVHTVVF
OrthoDBiEOG091G01CG
PhylomeDBiQ8R4B8

Family and domain databases

Gene3Di3.80.10.10, 1 hit
InterProiView protein in InterPro
IPR004020 DAPIN
IPR011029 DEATH-like_dom_sf
IPR001611 Leu-rich_rpt
IPR032675 LRR_dom_sf
IPR029495 NACHT-assoc
IPR007111 NACHT_NTPase
IPR027417 P-loop_NTPase
PfamiView protein in Pfam
PF14484 FISNA, 1 hit
PF13516 LRR_6, 5 hits
PF05729 NACHT, 1 hit
PF02758 PYRIN, 1 hit
SMARTiView protein in SMART
SM01288 FISNA, 1 hit
SM01289 PYRIN, 1 hit
SUPFAMiSSF47986 SSF47986, 1 hit
SSF52540 SSF52540, 2 hits
PROSITEiView protein in PROSITE
PS50824 DAPIN, 1 hit
PS51450 LRR, 5 hits
PS50837 NACHT, 1 hit

Sequences (4+)i

Sequence statusi: Complete.

This entry describes 4 isoformsi produced by alternative splicing. AlignAdd to basket

This entry has 4 described isoforms and 1 potential isoform that is computationally mapped.Show allAlign All

Isoform 1 (identifier: Q8R4B8-1) [UniParc]FASTAAdd to basket
Also known as: MMIG-1a

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide
        10         20         30         40         50
MTSVRCKLAQ YLEDLEDVDL KKFKMHLEDY PPEKGCIPVP RGQMEKADHL
60 70 80 90 100
DLATLMIDFN GEEKAWAMAV WIFAAINRRD LWEKAKKDQP EWNDTCTSHS
110 120 130 140 150
SMVCQEDSLE EEWMGLLGYL SRISICKKKK DYCKMYRRHV RSRFYSIKDR
160 170 180 190 200
NARLGESVDL NSRYTQLQLV KEHPSKQERE HELLTIGRTK MRDSPMSSLK
210 220 230 240 250
LELLFEPEDG HSEPVHTVVF QGAAGIGKTI LARKIMLDWA LGKLFKDKFD
260 270 280 290 300
YLFFIHCREV SLRTPRSLAD LIVSCWPDPN PPVCKILRKP SRILFLMDGF
310 320 330 340 350
DELQGAFDEH IGEVCTDWQK AVRGDILLSS LIRKKLLPKA SLLITTRPVA
360 370 380 390 400
LEKLQHLLDH PRHVEILGFS EAKRKEYFFK YFSNELQARE AFRLIQENEV
410 420 430 440 450
LFTMCFIPLV CWIVCTGLKQ QMETGKSLAQ TSKTTTAVYV FFLSSLLQSR
460 470 480 490 500
GGIEEHLFSD YLQGLCSLAA DGIWNQKILF EECDLRKHGL QKTDVSAFLR
510 520 530 540 550
MNVFQKEVDC ERFYSFSHMT FQEFFAAMYY LLEEEAEGET VRKGPGGCSD
560 570 580 590 600
LLNRDVKVLL ENYGKFEKGY LIFVVRFLFG LVNQERTSYL EKKLSCKISQ
610 620 630 640 650
QVRLELLKWI EVKAKAKKLQ WQPSQLELFY CLYEMQEEDF VQSAMDHFPK
660 670 680 690 700
IEINLSTRMD HVVSSFCIKN CHRVKTLSLG FFHNSPKEEE EERRGGRPLD
710 720 730 740 750
QVQCVFPDTH VACSSRLVNC CLTSSFCRGL FSSLSTNRSL TELDLSDNTL
760 770 780 790 800
GDPGMRVLCE ALQHPGCNIQ RLWLGRCGLS HQCCFDISSV LSSSQKLVEL
810 820 830 840 850
DLSDNALGDF GIRLLCVGLK HLLCNLQKLW LVSCCLTSAC CQDLALVLSS
860 870 880 890 900
NHSLTRLYIG ENALGDSGVQ VLCEKMKDPQ CNLQKLGLVN SGLTSICCSA
910 920 930 940 950
LTSVLKTNQN FTHLYLRSNA LGDTGLRLLC EGLLHPDCKL QMLELDNCSL
960 970 980 990 1000
TSHSCWNLST ILTHNHSLRK LNLGNNDLGD LCVVTLCEVL KQQGCLLQSL
1010 1020 1030
QLGEMYLNRE TKRALEALQE EKPELTIVFE ISW
Length:1,033
Mass (Da):118,275
Last modified:June 1, 2002 - v1
Checksum:i5924690966B12117
GO
Isoform 2 (identifier: Q8R4B8-2) [UniParc]FASTAAdd to basket
Also known as: MMIG-1b

The sequence of this isoform differs from the canonical sequence as follows:
     888-944: Missing.

Show »
Length:976
Mass (Da):112,073
Checksum:i01C3B9AC1D01C9D8
GO
Isoform 3 (identifier: Q8R4B8-3) [UniParc]FASTAAdd to basket
Also known as: MMIG-1c

The sequence of this isoform differs from the canonical sequence as follows:
     774-830: Missing.

Show »
Length:976
Mass (Da):112,032
Checksum:iC8D9FB1ECD871D5E
GO
Isoform 4 (identifier: Q8R4B8-4) [UniParc]FASTAAdd to basket
Also known as: MMIG-1d

The sequence of this isoform differs from the canonical sequence as follows:
     830-1033: Missing.

Show »
Length:829
Mass (Da):95,710
Checksum:i9F8A2ABC9CAE7004
GO

Computationally mapped potential isoform sequencesi

There is 1 potential isoform mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
Q5SXI6Q5SXI6_MOUSE
NACHT, LRR and PYD domains-containi...
Nlrp3
173Annotation score:

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti491Q → R in AGU01502 (Ref. 4) Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_014925774 – 830Missing in isoform 3. 1 PublicationAdd BLAST57
Alternative sequenceiVSP_014926830 – 1033Missing in isoform 4. 2 PublicationsAdd BLAST204
Alternative sequenceiVSP_014927888 – 944Missing in isoform 2. 1 PublicationAdd BLAST57

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF486632 mRNA Translation: AAL90874.1
AY495376 mRNA Translation: AAS75794.1
AY495377 mRNA Translation: AAS75795.1
AY337285 mRNA Translation: AAR03540.1
AY337292
, AY337286, AY337287, AY337288, AY337289, AY337290, AY337291 Genomic DNA Translation: AAR03541.1
AY337299
, AY337293, AY337294, AY337295, AY337296, AY337297, AY337298 Genomic DNA Translation: AAR03542.1
AY337306
, AY337300, AY337301, AY337302, AY337303, AY337304, AY337305 Genomic DNA Translation: AAR03543.1
AY355340 mRNA Translation: AAR14737.1
KF032621 mRNA Translation: AGU01502.1
AL592522 Genomic DNA Translation: CAI24551.1
BC116174 mRNA Translation: AAI16175.1
BC116175 mRNA Translation: AAI16176.1
CCDSiCCDS24771.1 [Q8R4B8-1]
RefSeqiNP_665826.1, NM_145827.3 [Q8R4B8-1]
XP_006532920.1, XM_006532857.1 [Q8R4B8-1]
XP_006532921.1, XM_006532858.1 [Q8R4B8-1]
UniGeneiMm.54174

Genome annotation databases

EnsembliENSMUST00000079476; ENSMUSP00000078440; ENSMUSG00000032691 [Q8R4B8-1]
ENSMUST00000101148; ENSMUSP00000098707; ENSMUSG00000032691 [Q8R4B8-1]
GeneIDi216799
KEGGimmu:216799
UCSCiuc007jeh.1 mouse [Q8R4B8-1]

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF486632 mRNA Translation: AAL90874.1
AY495376 mRNA Translation: AAS75794.1
AY495377 mRNA Translation: AAS75795.1
AY337285 mRNA Translation: AAR03540.1
AY337292
, AY337286, AY337287, AY337288, AY337289, AY337290, AY337291 Genomic DNA Translation: AAR03541.1
AY337299
, AY337293, AY337294, AY337295, AY337296, AY337297, AY337298 Genomic DNA Translation: AAR03542.1
AY337306
, AY337300, AY337301, AY337302, AY337303, AY337304, AY337305 Genomic DNA Translation: AAR03543.1
AY355340 mRNA Translation: AAR14737.1
KF032621 mRNA Translation: AGU01502.1
AL592522 Genomic DNA Translation: CAI24551.1
BC116174 mRNA Translation: AAI16175.1
BC116175 mRNA Translation: AAI16176.1
CCDSiCCDS24771.1 [Q8R4B8-1]
RefSeqiNP_665826.1, NM_145827.3 [Q8R4B8-1]
XP_006532920.1, XM_006532857.1 [Q8R4B8-1]
XP_006532921.1, XM_006532858.1 [Q8R4B8-1]
UniGeneiMm.54174

3D structure databases

ProteinModelPortaliQ8R4B8
SMRiQ8R4B8
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

DIPiDIP-60132N
IntActiQ8R4B8, 5 interactors
STRINGi10090.ENSMUSP00000078440

Chemistry databases

BindingDBiQ8R4B8
ChEMBLiCHEMBL3779755

PTM databases

iPTMnetiQ8R4B8
PhosphoSitePlusiQ8R4B8

Proteomic databases

PaxDbiQ8R4B8
PRIDEiQ8R4B8

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000079476; ENSMUSP00000078440; ENSMUSG00000032691 [Q8R4B8-1]
ENSMUST00000101148; ENSMUSP00000098707; ENSMUSG00000032691 [Q8R4B8-1]
GeneIDi216799
KEGGimmu:216799
UCSCiuc007jeh.1 mouse [Q8R4B8-1]

Organism-specific databases

CTDi114548
MGIiMGI:2653833 Nlrp3

Phylogenomic databases

eggNOGiENOG410IE5X Eukaryota
ENOG4111H3D LUCA
GeneTreeiENSGT00900000140813
HOGENOMiHOG000294064
HOVERGENiHBG063656
InParanoidiQ8R4B8
KOiK12800
OMAiPVHTVVF
OrthoDBiEOG091G01CG
PhylomeDBiQ8R4B8

Enzyme and pathway databases

ReactomeiR-MMU-5689901 Metalloprotease DUBs
R-MMU-844456 The NLRP3 inflammasome

Miscellaneous databases

PROiPR:Q8R4B8
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000032691 Expressed in 62 organ(s), highest expression level in spinal cord
CleanExiMM_NLRP3
ExpressionAtlasiQ8R4B8 baseline and differential
GenevisibleiQ8R4B8 MM

Family and domain databases

Gene3Di3.80.10.10, 1 hit
InterProiView protein in InterPro
IPR004020 DAPIN
IPR011029 DEATH-like_dom_sf
IPR001611 Leu-rich_rpt
IPR032675 LRR_dom_sf
IPR029495 NACHT-assoc
IPR007111 NACHT_NTPase
IPR027417 P-loop_NTPase
PfamiView protein in Pfam
PF14484 FISNA, 1 hit
PF13516 LRR_6, 5 hits
PF05729 NACHT, 1 hit
PF02758 PYRIN, 1 hit
SMARTiView protein in SMART
SM01288 FISNA, 1 hit
SM01289 PYRIN, 1 hit
SUPFAMiSSF47986 SSF47986, 1 hit
SSF52540 SSF52540, 2 hits
PROSITEiView protein in PROSITE
PS50824 DAPIN, 1 hit
PS51450 LRR, 5 hits
PS50837 NACHT, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiNLRP3_MOUSE
AccessioniPrimary (citable) accession number: Q8R4B8
Secondary accession number(s): Q1JQ87
, Q1JQ88, Q6JEL0, T1W2H6
Entry historyiIntegrated into UniProtKB/Swiss-Prot: March 28, 2003
Last sequence update: June 1, 2002
Last modified: September 12, 2018
This is version 157 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families
  2. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
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