ID NOX4_PONAB Reviewed; 578 AA.
AC Q5R5C5; Q5RCG3; Q5RE61;
DT 30-MAY-2006, integrated into UniProtKB/Swiss-Prot.
DT 30-MAY-2006, sequence version 2.
DT 27-MAR-2024, entry version 104.
DE RecName: Full=NADPH oxidase 4;
DE EC=1.6.3.1 {ECO:0000250|UniProtKB:Q9NPH5};
GN Name=NOX4;
OS Pongo abelii (Sumatran orangutan) (Pongo pygmaeus abelii).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Pongo.
OX NCBI_TaxID=9601;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Kidney;
RG The German cDNA consortium;
RL Submitted (NOV-2004) to the EMBL/GenBank/DDBJ databases.
CC -!- FUNCTION: NADPH oxidase that catalyzes predominantly the reduction of
CC oxygen to H2O2 (By similarity). Can also catalyze to a smaller extent,
CC the reduction of oxygen to superoxide (By similarity). May function as
CC an oxygen sensor regulating the KCNK3/TASK-1 potassium channel and
CC HIF1A activity (By similarity). May regulate insulin signaling cascade
CC (By similarity). May play a role in apoptosis, bone resorption and
CC lipolysaccharide-mediated activation of NFKB (By similarity). May
CC produce superoxide in the nucleus and play a role in regulating gene
CC expression upon cell stimulation (By similarity).
CC {ECO:0000250|UniProtKB:Q9NPH5}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=NADPH + 2 O2 = H(+) + NADP(+) + 2 superoxide;
CC Xref=Rhea:RHEA:63180, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:18421, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349;
CC Evidence={ECO:0000250|UniProtKB:Q9NPH5};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H(+) + NADPH + O2 = H2O2 + NADP(+); Xref=Rhea:RHEA:11260,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:15379, ChEBI:CHEBI:16240,
CC ChEBI:CHEBI:57783, ChEBI:CHEBI:58349; EC=1.6.3.1;
CC Evidence={ECO:0000250|UniProtKB:Q9NPH5};
CC -!- COFACTOR:
CC Name=heme; Xref=ChEBI:CHEBI:30413;
CC Evidence={ECO:0000250|UniProtKB:Q9NPH5};
CC -!- ACTIVITY REGULATION: Activated by insulin. Inhibited by diphenylene
CC iodonium. Inhibited by plumbagin. Activated by phorbol 12-myristate 13-
CC acetate (PMA) (By similarity). {ECO:0000250|UniProtKB:Q9JHI8,
CC ECO:0000250|UniProtKB:Q9NPH5}.
CC -!- SUBUNIT: Interacts with, relocalizes and stabilizes CYBA/p22phox.
CC Interacts with TLR4. Interacts with protein disulfide isomerase (By
CC similarity). Interacts with PPP1R15A (By similarity).
CC {ECO:0000250|UniProtKB:Q924V1, ECO:0000250|UniProtKB:Q9NPH5}.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC {ECO:0000250|UniProtKB:Q9NPH5}; Multi-pass membrane protein
CC {ECO:0000255}. Cell membrane {ECO:0000250|UniProtKB:Q9NPH5}; Multi-pass
CC membrane protein {ECO:0000255}. Cell junction, focal adhesion
CC {ECO:0000250|UniProtKB:Q924V1}. Nucleus {ECO:0000250|UniProtKB:Q9NPH5}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q5R5C5-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q5R5C5-2; Sequence=VSP_019065;
CC -!- PTM: N-glycosylation is required for the function.
CC {ECO:0000250|UniProtKB:Q9NPH5}.
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DR EMBL; CR857676; CAH89946.1; -; mRNA.
DR EMBL; CR858307; CAH90544.1; -; mRNA.
DR EMBL; CR860937; CAH93041.1; -; mRNA.
DR RefSeq; NP_001124912.1; NM_001131440.1.
DR RefSeq; NP_001128890.1; NM_001135418.1.
DR RefSeq; XP_009245205.1; XM_009246930.1. [Q5R5C5-1]
DR AlphaFoldDB; Q5R5C5; -.
DR SMR; Q5R5C5; -.
DR STRING; 9601.ENSPPYP00000004298; -.
DR GlyCosmos; Q5R5C5; 2 sites, No reported glycans.
DR Ensembl; ENSPPYT00000004472.3; ENSPPYP00000004298.2; ENSPPYG00000003756.3. [Q5R5C5-1]
DR Ensembl; ENSPPYT00000046242.1; ENSPPYP00000034182.1; ENSPPYG00000003756.3. [Q5R5C5-2]
DR GeneID; 100171782; -.
DR GeneID; 100189825; -.
DR KEGG; pon:100171782; -.
DR CTD; 50507; -.
DR eggNOG; KOG0039; Eukaryota.
DR GeneTree; ENSGT00940000159621; -.
DR HOGENOM; CLU_005646_3_1_1; -.
DR InParanoid; Q5R5C5; -.
DR OMA; AFWYTHQ; -.
DR OrthoDB; 367877at2759; -.
DR TreeFam; TF105354; -.
DR Proteomes; UP000001595; Chromosome 11.
DR GO; GO:0005783; C:endoplasmic reticulum; ISS:UniProtKB.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005925; C:focal adhesion; IEA:UniProtKB-SubCell.
DR GO; GO:0005739; C:mitochondrion; IEA:Ensembl.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:Ensembl.
DR GO; GO:0005886; C:plasma membrane; ISS:UniProtKB.
DR GO; GO:0020037; F:heme binding; ISS:UniProtKB.
DR GO; GO:0072341; F:modified amino acid binding; IEA:Ensembl.
DR GO; GO:0016174; F:NAD(P)H oxidase H2O2-forming activity; ISS:UniProtKB.
DR GO; GO:0106294; F:NADPH oxidase H202-forming activity; IEA:RHEA.
DR GO; GO:1990782; F:protein tyrosine kinase binding; IEA:Ensembl.
DR GO; GO:0016175; F:superoxide-generating NAD(P)H oxidase activity; ISS:UniProtKB.
DR GO; GO:0106292; F:superoxide-generating NADPH oxidase activity; IEA:RHEA.
DR GO; GO:0045453; P:bone resorption; IEA:Ensembl.
DR GO; GO:0055007; P:cardiac muscle cell differentiation; IEA:Ensembl.
DR GO; GO:0000902; P:cell morphogenesis; IEA:Ensembl.
DR GO; GO:0071333; P:cellular response to glucose stimulus; IEA:Ensembl.
DR GO; GO:0010467; P:gene expression; IEA:Ensembl.
DR GO; GO:0003015; P:heart process; IEA:Ensembl.
DR GO; GO:0050667; P:homocysteine metabolic process; IEA:Ensembl.
DR GO; GO:0008285; P:negative regulation of cell population proliferation; IEA:Ensembl.
DR GO; GO:2000573; P:positive regulation of DNA biosynthetic process; IEA:Ensembl.
DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IEA:Ensembl.
DR GO; GO:0051897; P:positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction; IEA:Ensembl.
DR GO; GO:0042554; P:superoxide anion generation; IEA:Ensembl.
DR CDD; cd06186; NOX_Duox_like_FAD_NADP; 1.
DR Gene3D; 3.40.50.80; Nucleotide-binding domain of ferredoxin-NADP reductase (FNR) module; 1.
DR Gene3D; 2.40.30.10; Translation factors; 1.
DR InterPro; IPR000778; Cyt_b245_heavy_chain.
DR InterPro; IPR013112; FAD-bd_8.
DR InterPro; IPR017927; FAD-bd_FR_type.
DR InterPro; IPR013130; Fe3_Rdtase_TM_dom.
DR InterPro; IPR013121; Fe_red_NAD-bd_6.
DR InterPro; IPR039261; FNR_nucleotide-bd.
DR InterPro; IPR017938; Riboflavin_synthase-like_b-brl.
DR PANTHER; PTHR11972; NADPH OXIDASE; 1.
DR PANTHER; PTHR11972:SF209; NADPH OXIDASE 4; 1.
DR Pfam; PF08022; FAD_binding_8; 1.
DR Pfam; PF01794; Ferric_reduct; 1.
DR Pfam; PF08030; NAD_binding_6; 1.
DR PRINTS; PR00466; GP91PHOX.
DR SUPFAM; SSF52343; Ferredoxin reductase-like, C-terminal NADP-linked domain; 1.
DR SUPFAM; SSF63380; Riboflavin synthase domain-like; 1.
DR PROSITE; PS51384; FAD_FR; 1.
PE 2: Evidence at transcript level;
KW Alternative splicing; Cell junction; Cell membrane; Disulfide bond;
KW Endoplasmic reticulum; Glycoprotein; Membrane; NADP; Nucleus;
KW Oxidoreductase; Reference proteome; Transmembrane; Transmembrane helix.
FT CHAIN 1..578
FT /note="NADPH oxidase 4"
FT /id="PRO_0000238982"
FT TOPO_DOM 1..16
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 17..37
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 38..62
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 63..83
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 84..103
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 104..124
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 125..154
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 155..175
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 176..188
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 189..209
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 210..424
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 425..445
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 446..578
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 58..303
FT /note="Ferric oxidoreductase"
FT DOMAIN 304..419
FT /note="FAD-binding FR-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00716"
FT REGION 218..273
FT /note="E-loop; essential for H2O2 generating catalytic
FT activity"
FT /evidence="ECO:0000250|UniProtKB:Q9NPH5"
FT REGION 248..575
FT /note="Mediates interaction with TLR4"
FT /evidence="ECO:0000250|UniProtKB:Q9NPH5"
FT CARBOHYD 133
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 230
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT VAR_SEQ 1..19
FT /note="MAVSWRSWLANEGVKHLCL -> MGEEVWRKREEVIFSEHSFSFYPLNIFAP
FT FVLFPDYFCLLE (in isoform 2)"
FT /evidence="ECO:0000303|Ref.1"
FT /id="VSP_019065"
FT CONFLICT 246
FT /note="H -> R (in Ref. 1; CAH90544/CAH89946)"
FT /evidence="ECO:0000305"
FT CONFLICT 306
FT /note="N -> D (in Ref. 1; CAH93041)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 578 AA; 66921 MW; C4D5C2839D617571 CRC64;
MAVSWRSWLA NEGVKHLCLF IWLSMNVLLF WKTFLLYNQG PEYHYLHQML GLGLCLSRAS
ASVLNLNCSL ILLPMCRTLL AYLRGSQKVP SRRTRRLLDK SRTFHITCGV TICIFSGVHV
AAHLVNALNF SVNYSEDFVE LNAARYRDED PRKLLFTTVP GLTGVCMVVV LFLMITASTY
AIRVSNYDIF WYTHNLFFVF YMLLTLHVSG GLLKYQTNLD THPPGCISLN RTSSQNISLP
EYFSEHFHEP FPEGFSKPEE FTQNTFVKIC MEEPRFQANF PQTWLWISGP LCLYCAERLY
RYIRSNKPVT IISVISHPSD VMEIRMVKEN FKARPGQYIT LHCPSVSALE NHPFTLTMCP
TETKATFGVH LKIVGDWTER FRDLLLPPSS QDSEILPFIQ SRNYPKLYID GPFGSPFEES
LNYEVSLCVA GGIGVTPFAS ILNTLLDDWK PYKLRRLYFI WVCRDIQSFR WFADLLCMLH
NKFWQENRPD YVNIQLYLSQ TDGIQKIIGE KYHALNSRLF IGRPRWKLLF DEIAKYNRGK
TVGVFCCGPN SLSKTLHKLS NQINSYGTRF EYNKESFS
//
