UniProtKB - Q9NPH5 (NOX4_HUMAN)
Protein
NADPH oxidase 4
Gene
NOX4
Organism
Homo sapiens (Human)
Status
Functioni
Constitutive NADPH oxidase which generates superoxide intracellularly upon formation of a complex with CYBA/p22phox. Regulates signaling cascades probably through phosphatases inhibition. May function as an oxygen sensor regulating the KCNK3/TASK-1 potassium channel and HIF1A activity. May regulate insulin signaling cascade. May play a role in apoptosis, bone resorption and lipolysaccharide-mediated activation of NFKB. May produce superoxide in the nucleus and play a role in regulating gene expression upon cell stimulation. Isoform 3 is not functional. Isoform 5 and isoform 6 display reduced activity.
Involved in redox signaling in vascular cells. Constitutively and NADPH-dependently generates reactive oxygen species (ROS). Modulates the nuclear activation of ERK1/2 and the ELK1 transcription factor, and is capable of inducing nuclear DNA damage. Displays an increased activity relative to isoform 1.
Activity regulationi
Inhibited by plumbagin (By similarity). Activated by phorbol 12-myristate 13-acetate (PMA). Activated by insulin. Inhibited by diphenylene iodonium.By similarity4 Publications
GO - Molecular functioni
- electron transfer activity Source: UniProtKB
- flavin adenine dinucleotide binding Source: UniProtKB
- heme binding Source: UniProtKB
- modified amino acid binding Source: UniProtKB
- NAD(P)H oxidase (H(2)O(2)-forming activity Source: UniProtKB
- nucleotide binding Source: UniProtKB
- oxygen sensor activity Source: UniProtKB
- protein tyrosine kinase binding Source: ARUK-UCL
- superoxide-generating NADPH oxidase activity Source: GO_Central
GO - Biological processi
- bone resorption Source: Ensembl
- cardiac muscle cell differentiation Source: Ensembl
- cell aging Source: UniProtKB
- cell morphogenesis Source: UniProtKB
- cellular response to cAMP Source: Ensembl
- cellular response to gamma radiation Source: Ensembl
- cellular response to glucose stimulus Source: Ensembl
- cellular response to oxidative stress Source: Reactome
- cellular response to transforming growth factor beta stimulus Source: Ensembl
- defense response Source: GO_Central
- gene expression Source: CACAO
- heart process Source: ARUK-UCL
- homocysteine metabolic process Source: UniProtKB
- inflammatory response Source: UniProtKB
- negative regulation of cell population proliferation Source: UniProtKB
- oxidation-reduction process Source: UniProtKB
- positive regulation of apoptotic process Source: Ensembl
- positive regulation of DNA biosynthetic process Source: Ensembl
- positive regulation of ERK1 and ERK2 cascade Source: Ensembl
- positive regulation of MAP kinase activity Source: Ensembl
- positive regulation of protein kinase B signaling Source: Ensembl
- positive regulation of protein tyrosine kinase activity Source: ARUK-UCL
- positive regulation of reactive oxygen species metabolic process Source: Ensembl
- positive regulation of smooth muscle cell migration Source: Ensembl
- positive regulation of stress fiber assembly Source: Ensembl
- reactive oxygen species biosynthetic process Source: ARUK-UCL
- reactive oxygen species metabolic process Source: UniProtKB
- response to hypoxia Source: Ensembl
- superoxide anion generation Source: UniProtKB
- superoxide metabolic process Source: CACAO
Keywordsi
Molecular function | Oxidoreductase |
Ligand | NADP |
Enzyme and pathway databases
PathwayCommonsi | Q9NPH5 |
Reactomei | R-HSA-3299685, Detoxification of Reactive Oxygen Species |
SIGNORi | Q9NPH5 |
Protein family/group databases
PeroxiBasei | 5967, HsNOx04 |
TCDBi | 5.B.1.1.2, the phagocyte (gp91(phox)) nadph oxidase family |
Names & Taxonomyi
Protein namesi | Recommended name: NADPH oxidase 4 (EC:1.6.3.-)Alternative name(s): Kidney oxidase-1 Short name: KOX-1 Kidney superoxide-producing NADPH oxidase Renal NAD(P)H-oxidase |
Gene namesi | Name:NOX4 Synonyms:RENOX |
Organismi | Homo sapiens (Human) |
Taxonomic identifieri | 9606 [NCBI] |
Taxonomic lineagei | Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo |
Proteomesi |
|
Organism-specific databases
EuPathDBi | HostDB:ENSG00000086991.12 |
HGNCi | HGNC:7891, NOX4 |
MIMi | 605261, gene |
neXtProti | NX_Q9NPH5 |
Subcellular locationi
Plasma membrane
- Cell membrane Curated; Multi-pass membrane protein Curated
Endoplasmic reticulum
Other locations
- focal adhesion Curated
Note: May localize to plasma membrane and focal adhesions. According to PubMed:15927447, may also localize to the nucleus.
Cytoskeleton
- stress fiber Source: Ensembl
Endoplasmic reticulum
- endoplasmic reticulum membrane Source: Reactome
- perinuclear endoplasmic reticulum Source: ARUK-UCL
Mitochondrion
- mitochondrion Source: ARUK-UCL
Nucleus
- nucleolus Source: UniProtKB-SubCell
- nucleoplasm Source: HPA
- nucleus Source: ARUK-UCL
Plasma Membrane
- apical plasma membrane Source: Ensembl
- NADPH oxidase complex Source: GO_Central
- plasma membrane Source: GO_Central
Other locations
- focal adhesion Source: UniProtKB-SubCell
- integral component of membrane Source: UniProtKB
- perinuclear region of cytoplasm Source: ARUK-UCL
Topology
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Topological domaini | 1 – 16 | CytoplasmicSequence analysisAdd BLAST | 16 | |
Transmembranei | 17 – 37 | HelicalSequence analysisAdd BLAST | 21 | |
Topological domaini | 38 – 62 | ExtracellularSequence analysisAdd BLAST | 25 | |
Transmembranei | 63 – 83 | HelicalSequence analysisAdd BLAST | 21 | |
Topological domaini | 84 – 103 | CytoplasmicSequence analysisAdd BLAST | 20 | |
Transmembranei | 104 – 124 | HelicalSequence analysisAdd BLAST | 21 | |
Topological domaini | 125 – 154 | ExtracellularSequence analysisAdd BLAST | 30 | |
Transmembranei | 155 – 175 | HelicalSequence analysisAdd BLAST | 21 | |
Topological domaini | 176 – 188 | CytoplasmicSequence analysisAdd BLAST | 13 | |
Transmembranei | 189 – 209 | HelicalSequence analysisAdd BLAST | 21 | |
Topological domaini | 210 – 424 | ExtracellularSequence analysisAdd BLAST | 215 | |
Transmembranei | 425 – 445 | HelicalSequence analysisAdd BLAST | 21 | |
Topological domaini | 446 – 578 | CytoplasmicSequence analysisAdd BLAST | 133 |
Keywords - Cellular componenti
Cell junction, Cell membrane, Endoplasmic reticulum, Membrane, NucleusPathology & Biotechi
Mutagenesis
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Mutagenesisi | 304 | R → RGT: Partial loss of catalytic activity. No effect on CYBA localization. 1 Publication | 1 | |
Mutagenesisi | 575 – 578 | Missing : Partial loss of catalytic activity. No effect on CYBA localization. 1 Publication | 4 |
Organism-specific databases
DisGeNETi | 50507 |
OpenTargetsi | ENSG00000086991 |
PharmGKBi | PA31692 |
Miscellaneous databases
Pharosi | Q9NPH5, Tchem |
Chemistry databases
ChEMBLi | CHEMBL1250375 |
DrugCentrali | Q9NPH5 |
GuidetoPHARMACOLOGYi | 3004 |
Polymorphism and mutation databases
BioMutai | NOX4 |
DMDMi | 212276447 |
PTM / Processingi
Molecule processing
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
ChainiPRO_0000238980 | 1 – 578 | NADPH oxidase 4Add BLAST | 578 |
Amino acid modifications
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Glycosylationi | 133 | N-linked (GlcNAc...) asparagineSequence analysis | 1 | |
Glycosylationi | 230 | N-linked (GlcNAc...) asparagineSequence analysis | 1 |
Post-translational modificationi
Isoform 3 and isoform 4 are N-glycosylated. Isoform 4 glycosylation is required for its proper function.1 Publication
Keywords - PTMi
Disulfide bond, GlycoproteinProteomic databases
MassIVEi | Q9NPH5 |
PaxDbi | Q9NPH5 |
PeptideAtlasi | Q9NPH5 |
PRIDEi | Q9NPH5 |
ProteomicsDBi | 16922 82003 [Q9NPH5-1] 82004 [Q9NPH5-2] 82005 [Q9NPH5-3] 82006 [Q9NPH5-4] 82007 [Q9NPH5-5] 82008 [Q9NPH5-6] 82009 [Q9NPH5-7] |
PTM databases
GlyGeni | Q9NPH5, 2 sites |
iPTMneti | Q9NPH5 |
PhosphoSitePlusi | Q9NPH5 |
Expressioni
Tissue specificityi
Expressed by distal tubular cells in kidney cortex and in endothelial cells (at protein level). Widely expressed. Strongly expressed in kidney and to a lower extent in heart, adipocytes, hepatoma, endothelial cells, skeletal muscle, brain, several brain tumor cell lines and airway epithelial cells.4 Publications
Developmental stagei
Expressed in fetal kidney and fetal liver.3 Publications
Inductioni
By 7-ketocholesterol (at protein level).1 Publication
Gene expression databases
Bgeei | ENSG00000086991, Expressed in calcaneal tendon and 144 other tissues |
ExpressionAtlasi | Q9NPH5, baseline and differential |
Genevisiblei | Q9NPH5, HS |
Organism-specific databases
HPAi | ENSG00000086991, Tissue enriched (kidney) |
Interactioni
Subunit structurei
Interacts with protein disulfide isomerase (By similarity).
Interacts with, relocalizes and stabilizes CYBA/p22phox.
Interacts with TLR4.
By similarity2 PublicationsBinary interactionsi
Q9NPH5
With | #Exp. | IntAct |
---|---|---|
TLR4 [O00206] | 4 | EBI-11301574,EBI-528701 |
GO - Molecular functioni
- protein tyrosine kinase binding Source: ARUK-UCL
Protein-protein interaction databases
BioGRIDi | 119078, 5 interactors |
IntActi | Q9NPH5, 3 interactors |
STRINGi | 9606.ENSP00000263317 |
Chemistry databases
BindingDBi | Q9NPH5 |
Miscellaneous databases
RNActi | Q9NPH5, protein |
Family & Domainsi
Domains and Repeats
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Domaini | 58 – 303 | Ferric oxidoreductaseAdd BLAST | 246 | |
Domaini | 304 – 419 | FAD-binding FR-typePROSITE-ProRule annotationAdd BLAST | 116 |
Region
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Regioni | 248 – 575 | Mediates interaction with TLR41 PublicationAdd BLAST | 328 |
Keywords - Domaini
Transmembrane, Transmembrane helixPhylogenomic databases
eggNOGi | KOG0039, Eukaryota |
GeneTreei | ENSGT00940000159621 |
HOGENOMi | CLU_005646_3_1_1 |
InParanoidi | Q9NPH5 |
OMAi | CKEDAHF |
OrthoDBi | 936110at2759 |
PhylomeDBi | Q9NPH5 |
TreeFami | TF105354 |
Family and domain databases
Gene3Di | 3.40.50.80, 1 hit |
InterProi | View protein in InterPro IPR000778, Cyt_b245_heavy_chain IPR013112, FAD-bd_8 IPR017927, FAD-bd_FR_type IPR013130, Fe3_Rdtase_TM_dom IPR013121, Fe_red_NAD-bd_6 IPR039261, FNR_nucleotide-bd IPR017938, Riboflavin_synthase-like_b-brl |
Pfami | View protein in Pfam PF08022, FAD_binding_8, 1 hit PF01794, Ferric_reduct, 1 hit PF08030, NAD_binding_6, 1 hit |
PRINTSi | PR00466, GP91PHOX |
SUPFAMi | SSF52343, SSF52343, 1 hit SSF63380, SSF63380, 1 hit |
PROSITEi | View protein in PROSITE PS51384, FAD_FR, 1 hit |
s (9+)i Sequence
Sequence statusi: Complete.
This entry describes 9 produced by isoformsialternative splicing. AlignAdd to basketThis entry has 9 described isoforms and 3 potential isoforms that are computationally mapped.Show allAlign All
Isoform 1 (identifier: Q9NPH5-1) [UniParc]FASTAAdd to basket
This isoform has been chosen as the sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry. canonicali
10 20 30 40 50
MAVSWRSWLA NEGVKHLCLF IWLSMNVLLF WKTFLLYNQG PEYHYLHQML
60 70 80 90 100
GLGLCLSRAS ASVLNLNCSL ILLPMCRTLL AYLRGSQKVP SRRTRRLLDK
110 120 130 140 150
SRTFHITCGV TICIFSGVHV AAHLVNALNF SVNYSEDFVE LNAARYRDED
160 170 180 190 200
PRKLLFTTVP GLTGVCMVVV LFLMITASTY AIRVSNYDIF WYTHNLFFVF
210 220 230 240 250
YMLLTLHVSG GLLKYQTNLD THPPGCISLN RTSSQNISLP EYFSEHFHEP
260 270 280 290 300
FPEGFSKPAE FTQHKFVKIC MEEPRFQANF PQTWLWISGP LCLYCAERLY
310 320 330 340 350
RYIRSNKPVT IISVMSHPSD VMEIRMVKEN FKARPGQYIT LHCPSVSALE
360 370 380 390 400
NHPFTLTMCP TETKATFGVH LKIVGDWTER FRDLLLPPSS QDSEILPFIQ
410 420 430 440 450
SRNYPKLYID GPFGSPFEES LNYEVSLCVA GGIGVTPFAS ILNTLLDDWK
460 470 480 490 500
PYKLRRLYFI WVCRDIQSFR WFADLLCMLH NKFWQENRPD YVNIQLYLSQ
510 520 530 540 550
TDGIQKIIGE KYHALNSRLF IGRPRWKLLF DEIAKYNRGK TVGVFCCGPN
560 570
SLSKTLHKLS NQNNSYGTRF EYNKESFS
Computationally mapped potential isoform sequencesi
There are 3 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basketE9PR43 | E9PR43_HUMAN | NADPH oxidase 4 | NOX4 | 391 | Annotation score: | ||
E9PPP2 | E9PPP2_HUMAN | NADPH oxidase 4 | NOX4 | 553 | Annotation score: | ||
E9PI95 | E9PI95_HUMAN | NADPH oxidase 4 | NOX4 | 342 | Annotation score: |
Experimental Info
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Sequence conflicti | 286 | W → C in BAH12756 (PubMed:14702039).Curated | 1 |
Natural variant
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Natural variantiVAR_047114 | 315 | M → I7 PublicationsCorresponds to variant dbSNP:rs317139Ensembl. | 1 |
Alternative sequence
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Alternative sequenceiVSP_019052 | 1 – 74 | Missing in isoform 2. 1 PublicationAdd BLAST | 74 | |
Alternative sequenceiVSP_053826 | 1 – 24 | Missing in isoform 8 and isoform 9. 1 PublicationAdd BLAST | 24 | |
Alternative sequenceiVSP_019053 | 52 – 358 | Missing in isoform 3 and isoform 4. 1 PublicationAdd BLAST | 307 | |
Alternative sequenceiVSP_019054 | 52 – 54 | LGL → ELS in isoform 7. 1 Publication | 3 | |
Alternative sequenceiVSP_019055 | 55 – 578 | Missing in isoform 7. 1 PublicationAdd BLAST | 524 | |
Alternative sequenceiVSP_019056 | 211 – 224 | GLLKY…DTHPP → VQLKPKQHLGFILK in isoform 5. 1 PublicationAdd BLAST | 14 | |
Alternative sequenceiVSP_019057 | 225 – 578 | Missing in isoform 5. 1 PublicationAdd BLAST | 354 | |
Alternative sequenceiVSP_019058 | 407 – 446 | Missing in isoform 3, isoform 6 and isoform 9. 3 PublicationsAdd BLAST | 40 |
Sequence databases
Genome annotation databases
Keywords - Coding sequence diversityi
Alternative splicing, PolymorphismSimilar proteinsi
Cross-referencesi
Sequence databases
3D structure databases
SMRi | Q9NPH5 |
ModBasei | Search... |
Protein-protein interaction databases
BioGRIDi | 119078, 5 interactors |
IntActi | Q9NPH5, 3 interactors |
STRINGi | 9606.ENSP00000263317 |
Chemistry databases
BindingDBi | Q9NPH5 |
ChEMBLi | CHEMBL1250375 |
DrugCentrali | Q9NPH5 |
GuidetoPHARMACOLOGYi | 3004 |
Protein family/group databases
PeroxiBasei | 5967, HsNOx04 |
TCDBi | 5.B.1.1.2, the phagocyte (gp91(phox)) nadph oxidase family |
PTM databases
GlyGeni | Q9NPH5, 2 sites |
iPTMneti | Q9NPH5 |
PhosphoSitePlusi | Q9NPH5 |
Polymorphism and mutation databases
BioMutai | NOX4 |
DMDMi | 212276447 |
Proteomic databases
MassIVEi | Q9NPH5 |
PaxDbi | Q9NPH5 |
PeptideAtlasi | Q9NPH5 |
PRIDEi | Q9NPH5 |
ProteomicsDBi | 16922 82003 [Q9NPH5-1] 82004 [Q9NPH5-2] 82005 [Q9NPH5-3] 82006 [Q9NPH5-4] 82007 [Q9NPH5-5] 82008 [Q9NPH5-6] 82009 [Q9NPH5-7] |
Protocols and materials databases
Antibodypediai | 17747, 609 antibodies |
DNASUi | 50507 |
Genome annotation databases
Organism-specific databases
CTDi | 50507 |
DisGeNETi | 50507 |
EuPathDBi | HostDB:ENSG00000086991.12 |
GeneCardsi | NOX4 |
HGNCi | HGNC:7891, NOX4 |
HPAi | ENSG00000086991, Tissue enriched (kidney) |
MIMi | 605261, gene |
neXtProti | NX_Q9NPH5 |
OpenTargetsi | ENSG00000086991 |
PharmGKBi | PA31692 |
GenAtlasi | Search... |
Phylogenomic databases
eggNOGi | KOG0039, Eukaryota |
GeneTreei | ENSGT00940000159621 |
HOGENOMi | CLU_005646_3_1_1 |
InParanoidi | Q9NPH5 |
OMAi | CKEDAHF |
OrthoDBi | 936110at2759 |
PhylomeDBi | Q9NPH5 |
TreeFami | TF105354 |
Enzyme and pathway databases
PathwayCommonsi | Q9NPH5 |
Reactomei | R-HSA-3299685, Detoxification of Reactive Oxygen Species |
SIGNORi | Q9NPH5 |
Miscellaneous databases
BioGRID-ORCSi | 50507, 4 hits in 849 CRISPR screens |
ChiTaRSi | NOX4, human |
GeneWikii | NOX4 |
GenomeRNAii | 50507 |
Pharosi | Q9NPH5, Tchem |
PROi | PR:Q9NPH5 |
RNActi | Q9NPH5, protein |
SOURCEi | Search... |
Gene expression databases
Bgeei | ENSG00000086991, Expressed in calcaneal tendon and 144 other tissues |
ExpressionAtlasi | Q9NPH5, baseline and differential |
Genevisiblei | Q9NPH5, HS |
Family and domain databases
Gene3Di | 3.40.50.80, 1 hit |
InterProi | View protein in InterPro IPR000778, Cyt_b245_heavy_chain IPR013112, FAD-bd_8 IPR017927, FAD-bd_FR_type IPR013130, Fe3_Rdtase_TM_dom IPR013121, Fe_red_NAD-bd_6 IPR039261, FNR_nucleotide-bd IPR017938, Riboflavin_synthase-like_b-brl |
Pfami | View protein in Pfam PF08022, FAD_binding_8, 1 hit PF01794, Ferric_reduct, 1 hit PF08030, NAD_binding_6, 1 hit |
PRINTSi | PR00466, GP91PHOX |
SUPFAMi | SSF52343, SSF52343, 1 hit SSF63380, SSF63380, 1 hit |
PROSITEi | View protein in PROSITE PS51384, FAD_FR, 1 hit |
ProtoNeti | Search... |
MobiDBi | Search... |
Entry informationi
Entry namei | NOX4_HUMAN | |
Accessioni | Q9NPH5Primary (citable) accession number: Q9NPH5 Secondary accession number(s): A8K715 Q86V92 | |
Entry historyi | Integrated into UniProtKB/Swiss-Prot: | May 30, 2006 |
Last sequence update: | November 4, 2008 | |
Last modified: | December 2, 2020 | |
This is version 158 of the entry and version 2 of the sequence. See complete history. | ||
Entry statusi | Reviewed (UniProtKB/Swiss-Prot) | |
Annotation program | Chordata Protein Annotation Program | |
Disclaimer | Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care. |
Miscellaneousi
Keywords - Technical termi
Reference proteomeDocuments
- Human polymorphisms and disease mutations
Index of human polymorphisms and disease mutations - MIM cross-references
Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot - Human chromosome 11
Human chromosome 11: entries, gene names and cross-references to MIM - Human entries with polymorphisms or disease mutations
List of human entries with polymorphisms or disease mutations