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Protein

NADPH oxidase 4

Gene

NOX4

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

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.
Isoform 4: 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.

Enzyme 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 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: Reactome

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
  • gene expression Source: CACAO
  • heart process Source: ARUK-UCL
  • homocysteine metabolic process Source: UniProtKB
  • inflammatory response Source: UniProtKB
  • negative regulation of cell 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 functionOxidoreductase
LigandNADP

Enzyme and pathway databases

ReactomeiR-HSA-3299685 Detoxification of Reactive Oxygen Species
SIGNORiQ9NPH5

Protein family/group databases

PeroxiBasei5967 HsNOx04
TCDBi5.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
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 11

Organism-specific databases

EuPathDBiHostDB:ENSG00000086991.12
HGNCiHGNC:7891 NOX4
MIMi605261 gene
neXtProtiNX_Q9NPH5

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

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini1 – 16CytoplasmicSequence analysisAdd BLAST16
Transmembranei17 – 37HelicalSequence analysisAdd BLAST21
Topological domaini38 – 62ExtracellularSequence analysisAdd BLAST25
Transmembranei63 – 83HelicalSequence analysisAdd BLAST21
Topological domaini84 – 103CytoplasmicSequence analysisAdd BLAST20
Transmembranei104 – 124HelicalSequence analysisAdd BLAST21
Topological domaini125 – 154ExtracellularSequence analysisAdd BLAST30
Transmembranei155 – 175HelicalSequence analysisAdd BLAST21
Topological domaini176 – 188CytoplasmicSequence analysisAdd BLAST13
Transmembranei189 – 209HelicalSequence analysisAdd BLAST21
Topological domaini210 – 424ExtracellularSequence analysisAdd BLAST215
Transmembranei425 – 445HelicalSequence analysisAdd BLAST21
Topological domaini446 – 578CytoplasmicSequence analysisAdd BLAST133

Keywords - Cellular componenti

Cell junction, Cell membrane, Endoplasmic reticulum, Membrane, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi304R → RGT: Partial loss of catalytic activity. No effect on CYBA localization. 1 Publication1
Mutagenesisi575 – 578Missing : Partial loss of catalytic activity. No effect on CYBA localization. 1 Publication4

Organism-specific databases

DisGeNETi50507
OpenTargetsiENSG00000086991
PharmGKBiPA31692

Chemistry databases

ChEMBLiCHEMBL1250375
GuidetoPHARMACOLOGYi3004

Polymorphism and mutation databases

BioMutaiNOX4
DMDMi212276447

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00002389801 – 578NADPH oxidase 4Add BLAST578

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Glycosylationi133N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi230N-linked (GlcNAc...) asparagineSequence analysis1

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, Glycoprotein

Proteomic databases

PaxDbiQ9NPH5
PeptideAtlasiQ9NPH5
PRIDEiQ9NPH5
ProteomicsDBi82003
82004 [Q9NPH5-2]
82005 [Q9NPH5-3]
82006 [Q9NPH5-4]
82007 [Q9NPH5-5]
82008 [Q9NPH5-6]
82009 [Q9NPH5-7]

PTM databases

iPTMnetiQ9NPH5
PhosphoSitePlusiQ9NPH5

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

BgeeiENSG00000086991
CleanExiHS_NOX4
ExpressionAtlasiQ9NPH5 baseline and differential
GenevisibleiQ9NPH5 HS

Organism-specific databases

HPAiHPA015475

Interactioni

Subunit structurei

Interacts with protein disulfide isomerase (By similarity). Interacts with, relocalizes and stabilizes CYBA/p22phox. Interacts with TLR4.By similarity2 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
TLR4O002064EBI-11301574,EBI-528701

GO - Molecular functioni

  • protein tyrosine kinase binding Source: ARUK-UCL

Protein-protein interaction databases

BioGridi119078, 2 interactors
IntActiQ9NPH5, 1 interactor
STRINGi9606.ENSP00000263317

Chemistry databases

BindingDBiQ9NPH5

Structurei

3D structure databases

ProteinModelPortaliQ9NPH5
SMRiQ9NPH5
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini58 – 303Ferric oxidoreductaseAdd BLAST246
Domaini304 – 419FAD-binding FR-typePROSITE-ProRule annotationAdd BLAST116

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni248 – 575Mediates interaction with TLR41 PublicationAdd BLAST328

Keywords - Domaini

Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG0039 Eukaryota
ENOG410XNZY LUCA
GeneTreeiENSGT00550000074350
HOGENOMiHOG000216669
HOVERGENiHBG003760
InParanoidiQ9NPH5
KOiK21423
OMAiFCCGPNS
OrthoDBiEOG091G09RV
PhylomeDBiQ9NPH5
TreeFamiTF105354

Family and domain databases

Gene3Di3.40.50.80, 1 hit
InterProiView protein in InterPro
IPR000778 Cyt_b245_heavy_chain
IPR013112 FAD-bd_8
IPR017927 Fd_Rdtase_FAD-bd
IPR013130 Fe3_Rdtase_TM_dom
IPR013121 Fe_red_NAD-bd_6
IPR039261 FNR_nucleotide_bd
IPR017938 Riboflavin_synthase-like_b-brl
PfamiView protein in Pfam
PF08022 FAD_binding_8, 1 hit
PF01794 Ferric_reduct, 1 hit
PF08030 NAD_binding_6, 1 hit
PRINTSiPR00466 GP91PHOX
SUPFAMiSSF52343 SSF52343, 1 hit
SSF63380 SSF63380, 1 hit
PROSITEiView protein in PROSITE
PS51384 FAD_FR, 1 hit

Sequences (9)i

Sequence statusi: Complete.

This entry describes 9 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q9NPH5-1) [UniParc]FASTAAdd to basket

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
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
Length:578
Mass (Da):66,932
Last modified:November 4, 2008 - v2
Checksum:iD150A92CC71DD40D
GO
Isoform 2 (identifier: Q9NPH5-2) [UniParc]FASTAAdd to basket
Also known as: Nox4A

The sequence of this isoform differs from the canonical sequence as follows:
     1-74: Missing.

Show »
Length:504
Mass (Da):58,410
Checksum:i5D1ECB62CB23ED47
GO
Isoform 3 (identifier: Q9NPH5-3) [UniParc]FASTAAdd to basket
Also known as: Nox4E

The sequence of this isoform differs from the canonical sequence as follows:
     52-358: Missing.
     407-446: Missing.

Show »
Length:231
Mass (Da):27,625
Checksum:i548F872E16DC4D37
GO
Isoform 4 (identifier: Q9NPH5-4) [UniParc]FASTAAdd to basket
Also known as: 28 kDa, Nox4D

The sequence of this isoform differs from the canonical sequence as follows:
     52-358: Missing.

Show »
Length:271
Mass (Da):31,812
Checksum:i9C889BAAB7E531A2
GO
Isoform 5 (identifier: Q9NPH5-5) [UniParc]FASTAAdd to basket
Also known as: Nox4C

The sequence of this isoform differs from the canonical sequence as follows:
     211-224: GLLKYQTNLDTHPP → VQLKPKQHLGFILK
     225-578: Missing.

Show »
Length:224
Mass (Da):25,761
Checksum:i27E3A0B6890E2A67
GO
Isoform 6 (identifier: Q9NPH5-6) [UniParc]FASTAAdd to basket
Also known as: Nox4B

The sequence of this isoform differs from the canonical sequence as follows:
     407-446: Missing.

Show »
Length:538
Mass (Da):62,745
Checksum:i2E541C48425EF25B
GO
Isoform 7 (identifier: Q9NPH5-7) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     52-54: LGL → ELS
     55-578: Missing.

Show »
Length:54
Mass (Da):6,516
Checksum:i2392A10568021769
GO
Isoform 8 (identifier: Q9NPH5-8) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-24: Missing.

Show »
Length:554
Mass (Da):64,102
Checksum:iD7469DB8BCE92821
GO
Isoform 9 (identifier: Q9NPH5-9) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-24: Missing.
     407-446: Missing.

Show »
Length:514
Mass (Da):59,915
Checksum:i5FFB5AA1DBE790B0
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti286W → C in BAH12756 (PubMed:14702039).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_047114315M → I7 PublicationsCorresponds to variant dbSNP:rs317139Ensembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0190521 – 74Missing in isoform 2. 1 PublicationAdd BLAST74
Alternative sequenceiVSP_0538261 – 24Missing in isoform 8 and isoform 9. 1 PublicationAdd BLAST24
Alternative sequenceiVSP_01905352 – 358Missing in isoform 3 and isoform 4. 1 PublicationAdd BLAST307
Alternative sequenceiVSP_01905452 – 54LGL → ELS in isoform 7. 1 Publication3
Alternative sequenceiVSP_01905555 – 578Missing in isoform 7. 1 PublicationAdd BLAST524
Alternative sequenceiVSP_019056211 – 224GLLKY…DTHPP → VQLKPKQHLGFILK in isoform 5. 1 PublicationAdd BLAST14
Alternative sequenceiVSP_019057225 – 578Missing in isoform 5. 1 PublicationAdd BLAST354
Alternative sequenceiVSP_019058407 – 446Missing in isoform 3, isoform 6 and isoform 9. 3 PublicationsAdd BLAST40

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF261943 mRNA Translation: AAF87572.1
AF254621 mRNA Translation: AAF68973.1
AB041035 mRNA Translation: BAA95695.1
AY288918 mRNA Translation: AAP41109.1
AJ704725 mRNA Translation: CAG28807.1
AJ704726 mRNA Translation: CAG28808.1
AJ704727 mRNA Translation: CAG28809.1
AJ704728 mRNA Translation: CAG28810.1
AJ704729 mRNA Translation: CAG28811.1
AK291830 mRNA Translation: BAF84519.1
AK298323 mRNA Translation: BAH12756.1
AP003400 Genomic DNA No translation available.
AP001815 Genomic DNA No translation available.
AP002404 Genomic DNA No translation available.
BC040105 mRNA Translation: AAH40105.1
BC051371 mRNA Translation: AAH51371.1
CCDSiCCDS44695.1 [Q9NPH5-6]
CCDS44696.1 [Q9NPH5-8]
CCDS73361.1 [Q9NPH5-9]
CCDS8285.1 [Q9NPH5-1]
RefSeqiNP_001137308.1, NM_001143836.2
NP_001137309.1, NM_001143837.1
NP_001278855.1, NM_001291926.1
NP_001278856.1, NM_001291927.1
NP_001287924.1, NM_001300995.1 [Q9NPH5-9]
NP_058627.1, NM_016931.4
XP_011541159.1, XM_011542857.2 [Q9NPH5-8]
UniGeneiHs.371036

Genome annotation databases

EnsembliENST00000263317; ENSP00000263317; ENSG00000086991 [Q9NPH5-1]
ENST00000343727; ENSP00000344747; ENSG00000086991 [Q9NPH5-8]
ENST00000375979; ENSP00000365146; ENSG00000086991 [Q9NPH5-4]
ENST00000393282; ENSP00000376961; ENSG00000086991 [Q9NPH5-7]
ENST00000424319; ENSP00000412446; ENSG00000086991 [Q9NPH5-8]
ENST00000527956; ENSP00000433797; ENSG00000086991 [Q9NPH5-8]
ENST00000529343; ENSP00000435474; ENSG00000086991 [Q9NPH5-5]
ENST00000531342; ENSP00000435039; ENSG00000086991 [Q9NPH5-3]
ENST00000532825; ENSP00000434924; ENSG00000086991 [Q9NPH5-9]
ENST00000534731; ENSP00000436892; ENSG00000086991 [Q9NPH5-6]
GeneIDi50507
KEGGihsa:50507
UCSCiuc001pct.4 human [Q9NPH5-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Entry informationi

Entry nameiNOX4_HUMAN
AccessioniPrimary (citable) accession number: Q9NPH5
Secondary accession number(s): A8K715
, B7Z520, E7EMD7, Q5K3R4, Q5K3R5, Q5K3R6, Q5K3R8, Q7Z7G3, Q86V92
Entry historyiIntegrated into UniProtKB/Swiss-Prot: May 30, 2006
Last sequence update: November 4, 2008
Last modified: July 18, 2018
This is version 140 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny 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

Complete proteome, Reference proteome

Documents

  1. Human chromosome 11
    Human chromosome 11: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

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