ID NOS2_RAT Reviewed; 1147 AA. AC Q06518; O35765; O35766; O60591; O60604; P97774; Q63267; Q64005; Q64558; DT 01-JUN-1994, integrated into UniProtKB/Swiss-Prot. DT 01-OCT-1996, sequence version 2. DT 24-JAN-2024, entry version 213. DE RecName: Full=Nitric oxide synthase, inducible; DE EC=1.14.13.39 {ECO:0000250|UniProtKB:P35228}; DE AltName: Full=Inducible NO synthase; DE Short=Inducible NOS; DE Short=iNOS; DE AltName: Full=NOS type II; DE AltName: Full=Peptidyl-cysteine S-nitrosylase NOS2; GN Name=Nos2; OS Rattus norvegicus (Rat). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; OC Murinae; Rattus. OX NCBI_TaxID=10116; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Vascular smooth muscle; RX PubMed=7680561; DOI=10.1006/bbrc.1993.1188; RA Nunokawa Y., Ishida N., Tanaka S.; RT "Cloning of inducible nitric oxide synthase in rat vascular smooth muscle RT cells."; RL Biochem. Biophys. Res. Commun. 191:89-94(1993). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA]. RC STRAIN=Wistar; TISSUE=Pancreatic islet; RX PubMed=7540573; DOI=10.2337/diab.44.7.753; RA Karlsen A.E., Andersen H.U., Vissing H., Larsen P.M., Fey S.J., RA Cuartero B.G., Madsen O.D., Petersen J.S., Mortensen S.B., RA Mandrup-Poulsen T., Boel E., Nerup J.; RT "Cloning and expression of cytokine-inducible nitric oxide synthase cDNA RT from rat islets of Langerhans."; RL Diabetes 44:753-758(1995). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA]. RC STRAIN=Sprague-Dawley; TISSUE=Astrocyte; RX PubMed=7513765; DOI=10.1002/jnr.490370313; RA Galea E., Reis D.J., Feinstein D.L.; RT "Cloning and expression of inducible nitric oxide synthase from rat RT astrocytes."; RL J. Neurosci. Res. 37:406-414(1994). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA], AND PARTIAL PROTEIN SEQUENCE. RC TISSUE=Liver; RX PubMed=7693462; DOI=10.1111/j.1432-1033.1993.tb18215.x; RA Adachi H., Iida S., Oguchi S., Ohshima H., Suzuki H., Nagasaki K., RA Kawasaki H., Sugimura T., Esumi H.; RT "Molecular cloning of a cDNA encoding an inducible calmodulin-dependent RT nitric-oxide synthase from rat liver and its expression in COS 1 cells."; RL Eur. J. Biochem. 217:37-43(1993). RN [5] RP NUCLEOTIDE SEQUENCE [MRNA]. RC STRAIN=Sprague-Dawley; TISSUE=Hepatocyte; RX PubMed=7682072; DOI=10.1006/bbrc.1993.1283; RA Wood E.R., Berger H. Jr., Sherman P.A., Lapetina E.G.; RT "Hepatocytes and macrophages express an identical cytokine inducible nitric RT oxide synthase gene."; RL Biochem. Biophys. Res. Commun. 191:767-774(1993). RN [6] RP NUCLEOTIDE SEQUENCE [MRNA]. RC STRAIN=Sprague-Dawley; TISSUE=Aorta; RX PubMed=7519448; DOI=10.1016/0167-4781(94)90196-1; RA Geng Y.J., Almquist M., Hansson G.K.; RT "cDNA cloning and expression of inducible nitric oxide synthase from rat RT vascular smooth muscle cells."; RL Biochim. Biophys. Acta 1218:421-424(1994). RN [7] RP NUCLEOTIDE SEQUENCE [MRNA]. RA Kosuga K., Yui Y., Hattori R., Sase K., Eizawa H., Aoyama T., Inoue R., RA Sasayama S.; RT "Cloning of an inducible nitric oxide synthase from rat polymorphonuclear RT neutrophils."; RL Endothelium 2:217-221(1994). RN [8] RP NUCLEOTIDE SEQUENCE [MRNA]. RX PubMed=8913516; DOI=10.1248/bpb.19.1374; RA Tsutsumishita Y., Kawai Y., Takahara H., Onda T., Miyoshi J., Futaki S., RA Niwa M.; RT "Sequence analysis of inducible nitric oxide synthase in rat kidney, lung, RT and uterus."; RL Biol. Pharm. Bull. 19:1374-1376(1996). RN [9] RP NUCLEOTIDE SEQUENCE [MRNA]. RX PubMed=9851365; DOI=10.1006/niox.1998.0184; RA Adams V., Krabbes S., Jiang H., Yu J., Rahmel A., Gielen S., Schuler G., RA Hambrecht R.; RT "Complete coding sequence of inducible nitric oxide synthase from human RT heart and skeletal muscle of patients with chronic heart failure."; RL Nitric Oxide 2:242-249(1998). RN [10] RP NUCLEOTIDE SEQUENCE [MRNA] OF 426-788. RC STRAIN=Dahl/Rapp salt sensitive strain; TISSUE=Vascular smooth muscle; RX PubMed=9535415; DOI=10.1161/01.hyp.31.4.918; RA Chen P.Y., Gladish R.D., Sanders P.W.; RT "Vascular smooth muscle nitric oxide synthase anomalies in Dahl/Rapp salt- RT sensitive rats."; RL Hypertension 31:918-924(1998). RN [11] RP NUCLEOTIDE SEQUENCE [MRNA] OF 509-740. RC STRAIN=Wistar; TISSUE=Renal glomerulus; RA Saura M., Zaragoza C., Martinez-Dalmau R., Perez-Sala D., Lamas S.; RT "Advances in the studies of NO synthesis regulation in mesanglial cells."; RL Nefrologia 16:35-39(1996). RN [12] RP NUCLEOTIDE SEQUENCE [MRNA] OF 479-655. RC STRAIN=Sprague-Dawley; TISSUE=Renal glomerulus; RX PubMed=7516453; DOI=10.1038/ki.1994.135; RA Morrissey J.J., McCracken R., Kaneto H., Vehaskari M., Montani D., RA Klahr S.; RT "Location of an inducible nitric oxide synthase mRNA in the normal RT kidney."; RL Kidney Int. 45:998-1005(1994). RN [13] RP NUCLEOTIDE SEQUENCE [MRNA] OF 420-479. RC TISSUE=Myocardium; RA Michel T., Balligand J.-L.; RT "Isolation and characterization of iNOS from rat cardiocytes."; RL Submitted (SEP-1994) to the EMBL/GenBank/DDBJ databases. RN [14] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-564 AND TYR-572, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=16641100; DOI=10.1073/pnas.0600895103; RA Hoffert J.D., Pisitkun T., Wang G., Shen R.-F., Knepper M.A.; RT "Quantitative phosphoproteomics of vasopressin-sensitive renal cells: RT regulation of aquaporin-2 phosphorylation at two sites."; RL Proc. Natl. Acad. Sci. U.S.A. 103:7159-7164(2006). CC -!- FUNCTION: Produces nitric oxide (NO) which is a messenger molecule with CC diverse functions throughout the body. In macrophages, NO mediates CC tumoricidal and bactericidal actions. Also has nitrosylase activity and CC mediates cysteine S-nitrosylation of cytoplasmic target proteins such CC PTGS2/COX2. As component of the iNOS-S100A8/9 transnitrosylase complex CC involved in the selective inflammatory stimulus-dependent S- CC nitrosylation of GAPDH implicated in regulation of the GAIT complex CC activity and probably multiple targets including ANXA5, EZR, MSN and CC VIM. Involved in inflammation, enhances the synthesis of pro- CC inflammatory mediators such as IL6 and IL8. CC {ECO:0000250|UniProtKB:P29477, ECO:0000250|UniProtKB:P35228}. CC -!- CATALYTIC ACTIVITY: CC Reaction=H(+) + 2 L-arginine + 3 NADPH + 4 O2 = 4 H2O + 2 L-citrulline CC + 3 NADP(+) + 2 nitric oxide; Xref=Rhea:RHEA:19897, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379, CC ChEBI:CHEBI:16480, ChEBI:CHEBI:32682, ChEBI:CHEBI:57743, CC ChEBI:CHEBI:57783, ChEBI:CHEBI:58349; EC=1.14.13.39; CC Evidence={ECO:0000250|UniProtKB:P35228}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:19898; CC Evidence={ECO:0000250|UniProtKB:P35228}; CC -!- COFACTOR: CC Name=heme b; Xref=ChEBI:CHEBI:60344; CC Evidence={ECO:0000250|UniProtKB:P35228}; CC -!- COFACTOR: CC Name=FAD; Xref=ChEBI:CHEBI:57692; CC Evidence={ECO:0000250|UniProtKB:P29476}; CC Note=Binds 1 FAD. {ECO:0000250|UniProtKB:P29476}; CC -!- COFACTOR: CC Name=FMN; Xref=ChEBI:CHEBI:58210; CC Evidence={ECO:0000250|UniProtKB:P35228}; CC Note=Binds 1 FMN. {ECO:0000250|UniProtKB:P35228}; CC -!- COFACTOR: CC Name=(6R)-L-erythro-5,6,7,8-tetrahydrobiopterin; CC Xref=ChEBI:CHEBI:59560; Evidence={ECO:0000250|UniProtKB:P35228}; CC Note=Tetrahydrobiopterin (BH4). May stabilize the dimeric form of the CC enzyme. {ECO:0000250|UniProtKB:P35228}; CC -!- ACTIVITY REGULATION: Not stimulated by calcium/calmodulin. Aspirin CC inhibits expression and function of this enzyme and effects may be CC exerted at the level of translational/post-translational modification CC and directly on the catalytic activity (By similarity). {ECO:0000250}. CC -!- SUBUNIT: Homodimer. Interacts with NHERF1. Interacts with GAPDH; CC induced by oxidatively-modified low-densitity lipoprotein (LDL(ox)). CC Interacts with S100A8 and S100A9 to form the iNOS-S100A8/9 CC transnitrosylase complex. Interacts with SPSB1, SPSB2 and SPSB4. CC Interacts with ELOC and CUL5 in the presence of SPSB1 or SPSB2 or CC SPSB4. Forms a complex with ASL, ASS1 and HSP90AA1; the complex CC regulates cell-autonomous L-arginine synthesis and citrulline recycling CC while channeling extracellular L-arginine to nitric oxide synthesis CC pathway. {ECO:0000250|UniProtKB:P29477}. CC -!- INTERACTION: CC Q06518; Q7TQN4: Rela; NbExp=3; IntAct=EBI-15919967, EBI-1187180; CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol CC {ECO:0000250|UniProtKB:P35228}. Note=Localizes as discrete foci CC scattered throughout the cytosol and in the presence of SPSB1 and CC SPSB4, exhibits a more diffuse cytosolic localization. CC {ECO:0000250|UniProtKB:P35228}. CC -!- TISSUE SPECIFICITY: In normal kidney, expressed primarily in the CC medullary thick ascending limb, with minor amounts in the medullary CC collecting duct and vasa recta bundle. CC -!- INDUCTION: By interferon gamma and lipopolysaccharides (LPS). CC -!- PTM: Polyubiquitinated; mediated by SPSB1, SPSB2 and SPSB4, leading to CC proteasomal degradation. {ECO:0000250|UniProtKB:P35228}. CC -!- SIMILARITY: Belongs to the NOS family. {ECO:0000305}. CC -!- CAUTION: sequence Was originally thought to originate from human but CC appears to be from rat. {ECO:0000305|PubMed:9851365}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; D14051; BAA03138.1; -; mRNA. DR EMBL; U26686; AAA85861.1; -; mRNA. DR EMBL; U03699; AAC13747.1; -; mRNA. DR EMBL; D12520; BAA02090.1; -; mRNA. DR EMBL; L12562; AAA41720.1; -; mRNA. DR EMBL; X76881; CAA54208.1; -; mRNA. DR EMBL; D44591; BAA07994.1; -; mRNA. DR EMBL; D83661; BAA12035.1; -; mRNA. DR EMBL; AF049656; AAC83553.1; -; mRNA. DR EMBL; AF051164; AAC83554.1; -; mRNA. DR EMBL; AF006619; AAC16401.1; -; mRNA. DR EMBL; AF006620; AAC16402.1; -; mRNA. DR EMBL; U48829; AAB18620.1; -; mRNA. DR EMBL; S71597; AAB31028.2; -; mRNA. DR EMBL; L36063; AAC02242.1; -; mRNA. DR PIR; I53165; I53165. DR PIR; I56575; I56575. DR PIR; JC5027; JC5027. DR PIR; S38253; S38253. DR PIR; S47647; S47647. DR RefSeq; NP_036743.3; NM_012611.3. DR AlphaFoldDB; Q06518; -. DR SMR; Q06518; -. DR CORUM; Q06518; -. DR DIP; DIP-59942N; -. DR IntAct; Q06518; 1. DR STRING; 10116.ENSRNOP00000067662; -. DR BindingDB; Q06518; -. DR ChEMBL; CHEMBL3051; -. DR iPTMnet; Q06518; -. DR PhosphoSitePlus; Q06518; -. DR PaxDb; 10116-ENSRNOP00000067662; -. DR Ensembl; ENSRNOT00055043587; ENSRNOP00055035578; ENSRNOG00055025134. DR Ensembl; ENSRNOT00060033771; ENSRNOP00060027661; ENSRNOG00060019106. DR GeneID; 24599; -. DR KEGG; rno:24599; -. DR AGR; RGD:3185; -. DR CTD; 4843; -. DR RGD; 3185; Nos2. DR eggNOG; KOG1158; Eukaryota. DR InParanoid; Q06518; -. DR OrthoDB; 276396at2759; -. DR PhylomeDB; Q06518; -. DR BRENDA; 1.14.13.39; 5301. DR Reactome; R-RNO-1222556; ROS and RNS production in phagocytes. DR Reactome; R-RNO-392154; Nitric oxide stimulates guanylate cyclase. DR Reactome; R-RNO-9033241; Peroxisomal protein import. DR PRO; PR:Q06518; -. DR Proteomes; UP000002494; Unplaced. DR GO; GO:0030863; C:cortical cytoskeleton; ISO:RGD. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:UniProtKB. DR GO; GO:0005615; C:extracellular space; IDA:RGD. DR GO; GO:0005634; C:nucleus; IDA:BHF-UCL. DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:RGD. DR GO; GO:0005777; C:peroxisome; IDA:UniProtKB. DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central. DR GO; GO:0003779; F:actin binding; IDA:RGD. DR GO; GO:0034618; F:arginine binding; ISO:RGD. DR GO; GO:0008013; F:beta-catenin binding; IPI:RGD. DR GO; GO:0045296; F:cadherin binding; IPI:RGD. DR GO; GO:0005516; F:calmodulin binding; IEA:UniProtKB-KW. DR GO; GO:0008603; F:cAMP-dependent protein kinase regulator activity; IDA:RGD. DR GO; GO:0050660; F:flavin adenine dinucleotide binding; ISO:RGD. DR GO; GO:0010181; F:FMN binding; ISO:RGD. DR GO; GO:0020037; F:heme binding; ISO:RGD. DR GO; GO:0051879; F:Hsp90 protein binding; IDA:RGD. DR GO; GO:0042802; F:identical protein binding; IPI:RGD. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW. DR GO; GO:0050661; F:NADP binding; IEA:InterPro. DR GO; GO:0004517; F:nitric-oxide synthase activity; IDA:RGD. DR GO; GO:0050998; F:nitric-oxide synthase binding; IPI:RGD. DR GO; GO:0042803; F:protein homodimerization activity; ISO:RGD. DR GO; GO:0019901; F:protein kinase binding; IPI:RGD. DR GO; GO:0034617; F:tetrahydrobiopterin binding; ISO:RGD. DR GO; GO:0006527; P:arginine catabolic process; ISO:RGD. DR GO; GO:0001974; P:blood vessel remodeling; IMP:RGD. DR GO; GO:0071345; P:cellular response to cytokine stimulus; IDA:MGI. DR GO; GO:0071347; P:cellular response to interleukin-1; IEP:RGD. DR GO; GO:0071222; P:cellular response to lipopolysaccharide; IEP:RGD. DR GO; GO:0071285; P:cellular response to lithium ion; IEP:RGD. DR GO; GO:0071407; P:cellular response to organic cyclic compound; IDA:MGI. DR GO; GO:0071461; P:cellular response to redox state; IEP:RGD. DR GO; GO:0071356; P:cellular response to tumor necrosis factor; IEP:RGD. DR GO; GO:0071346; P:cellular response to type II interferon; ISO:RGD. DR GO; GO:0071305; P:cellular response to vitamin D; IEP:RGD. DR GO; GO:0071466; P:cellular response to xenobiotic stimulus; ISO:RGD. DR GO; GO:0019934; P:cGMP-mediated signaling; IDA:RGD. DR GO; GO:0007623; P:circadian rhythm; ISO:RGD. DR GO; GO:0042742; P:defense response to bacterium; ISS:UniProtKB. DR GO; GO:0050829; P:defense response to Gram-negative bacterium; IEP:RGD. DR GO; GO:0001935; P:endothelial cell proliferation; IEP:RGD. DR GO; GO:0007199; P:G protein-coupled receptor signaling pathway coupled to cGMP nucleotide second messenger; IDA:RGD. DR GO; GO:0016137; P:glycoside metabolic process; IEP:RGD. DR GO; GO:0006954; P:inflammatory response; IBA:GO_Central. DR GO; GO:0035556; P:intracellular signal transduction; IMP:RGD. DR GO; GO:0045776; P:negative regulation of blood pressure; IBA:GO_Central. DR GO; GO:0010629; P:negative regulation of gene expression; ISO:RGD. DR GO; GO:0042177; P:negative regulation of protein catabolic process; ISO:RGD. DR GO; GO:0006809; P:nitric oxide biosynthetic process; IDA:RGD. DR GO; GO:0007263; P:nitric oxide mediated signal transduction; IBA:GO_Central. DR GO; GO:0018119; P:peptidyl-cysteine S-nitrosylation; ISS:UniProtKB. DR GO; GO:0043065; P:positive regulation of apoptotic process; IMP:RGD. DR GO; GO:0032755; P:positive regulation of interleukin-6 production; ISS:UniProtKB. DR GO; GO:0032757; P:positive regulation of interleukin-8 production; ISS:UniProtKB. DR GO; GO:0051712; P:positive regulation of killing of cells of another organism; ISO:RGD. DR GO; GO:0032310; P:prostaglandin secretion; ISS:UniProtKB. DR GO; GO:0008217; P:regulation of blood pressure; IMP:RGD. DR GO; GO:0042127; P:regulation of cell population proliferation; ISO:RGD. DR GO; GO:1900015; P:regulation of cytokine production involved in inflammatory response; ISS:UniProtKB. DR GO; GO:0050796; P:regulation of insulin secretion; ISO:RGD. DR GO; GO:0014823; P:response to activity; IEP:RGD. DR GO; GO:0009617; P:response to bacterium; ISO:RGD. DR GO; GO:0071548; P:response to dexamethasone; IEP:RGD. DR GO; GO:0032355; P:response to estradiol; IEP:RGD. DR GO; GO:0009750; P:response to fructose; IEP:RGD. DR GO; GO:0009749; P:response to glucose; IEP:RGD. DR GO; GO:0009725; P:response to hormone; IEP:RGD. DR GO; GO:0001666; P:response to hypoxia; ISO:RGD. DR GO; GO:0035902; P:response to immobilization stress; IEP:RGD. DR GO; GO:0032496; P:response to lipopolysaccharide; IEP:RGD. DR GO; GO:0009612; P:response to mechanical stimulus; IEP:RGD. DR GO; GO:0090649; P:response to oxygen-glucose deprivation; IEP:RGD. DR GO; GO:0034612; P:response to tumor necrosis factor; IMP:RGD. DR GO; GO:0048384; P:retinoic acid receptor signaling pathway; IEP:RGD. DR GO; GO:0006801; P:superoxide metabolic process; ISS:UniProtKB. DR CDD; cd00795; NOS_oxygenase_euk; 1. DR Gene3D; 3.40.50.360; -; 2. DR Gene3D; 6.10.250.410; -; 1. DR Gene3D; 3.90.440.10; Nitric Oxide Synthase;Heme Domain;Chain A domain 2; 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; IPR003097; CysJ-like_FAD-binding. DR InterPro; IPR017927; FAD-bd_FR_type. DR InterPro; IPR001094; Flavdoxin-like. DR InterPro; IPR008254; Flavodoxin/NO_synth. DR InterPro; IPR001709; Flavoprot_Pyr_Nucl_cyt_Rdtase. DR InterPro; IPR029039; Flavoprotein-like_sf. DR InterPro; IPR039261; FNR_nucleotide-bd. DR InterPro; IPR023173; NADPH_Cyt_P450_Rdtase_alpha. DR InterPro; IPR044943; NOS_dom_1. DR InterPro; IPR044940; NOS_dom_2. DR InterPro; IPR044944; NOS_dom_3. DR InterPro; IPR012144; NOS_euk. DR InterPro; IPR004030; NOS_N. DR InterPro; IPR036119; NOS_N_sf. DR InterPro; IPR001433; OxRdtase_FAD/NAD-bd. DR InterPro; IPR017938; Riboflavin_synthase-like_b-brl. DR PANTHER; PTHR43410; NITRIC OXIDE SYNTHASE OXYGENASE; 1. DR PANTHER; PTHR43410:SF1; NITRIC OXIDE SYNTHASE OXYGENASE; 1. DR Pfam; PF00667; FAD_binding_1; 1. DR Pfam; PF00258; Flavodoxin_1; 1. DR Pfam; PF00175; NAD_binding_1; 1. DR Pfam; PF02898; NO_synthase; 1. DR PIRSF; PIRSF000333; NOS; 1. DR PRINTS; PR00369; FLAVODOXIN. DR PRINTS; PR00371; FPNCR. DR SUPFAM; SSF52343; Ferredoxin reductase-like, C-terminal NADP-linked domain; 1. DR SUPFAM; SSF52218; Flavoproteins; 1. DR SUPFAM; SSF56512; Nitric oxide (NO) synthase oxygenase domain; 1. DR SUPFAM; SSF63380; Riboflavin synthase domain-like; 1. DR PROSITE; PS51384; FAD_FR; 1. DR PROSITE; PS50902; FLAVODOXIN_LIKE; 1. DR PROSITE; PS60001; NOS; 1. PE 1: Evidence at protein level; KW Calmodulin-binding; Cytoplasm; Direct protein sequencing; FAD; KW Flavoprotein; FMN; Heme; Iron; Metal-binding; NADP; Oxidoreductase; KW Phosphoprotein; Reference proteome; Ubl conjugation; Zinc. FT CHAIN 1..1147 FT /note="Nitric oxide synthase, inducible" FT /id="PRO_0000170937" FT DOMAIN 536..674 FT /note="Flavodoxin-like" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00088" FT DOMAIN 727..967 FT /note="FAD-binding FR-type" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00716" FT REGION 22..51 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 512..532 FT /note="Calmodulin-binding" FT /evidence="ECO:0000250|UniProtKB:P35228" FT MOTIF 23..27 FT /note="DINNN-motif; mediates interaction with SPSB1, SPSB2 FT and SPSB4" FT /evidence="ECO:0000250|UniProtKB:P35228" FT BINDING 107 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_note="ligand shared between homodimeric partners" FT /evidence="ECO:0000250|UniProtKB:P35228" FT BINDING 112 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_note="ligand shared between homodimeric partners" FT /evidence="ECO:0000250|UniProtKB:P35228" FT BINDING 115 FT /ligand="(6R)-L-erythro-5,6,7,8-tetrahydrobiopterin" FT /ligand_id="ChEBI:CHEBI:59560" FT /evidence="ECO:0000250|UniProtKB:P29474" FT BINDING 197 FT /ligand="heme b" FT /ligand_id="ChEBI:CHEBI:60344" FT /ligand_part="Fe" FT /ligand_part_id="ChEBI:CHEBI:18248" FT /note="axial binding residue" FT /evidence="ECO:0000250|UniProtKB:P29474" FT BINDING 260 FT /ligand="L-arginine" FT /ligand_id="ChEBI:CHEBI:32682" FT /evidence="ECO:0000250|UniProtKB:P29474" FT BINDING 369 FT /ligand="L-arginine" FT /ligand_id="ChEBI:CHEBI:32682" FT /evidence="ECO:0000250|UniProtKB:P29474" FT BINDING 370 FT /ligand="L-arginine" FT /ligand_id="ChEBI:CHEBI:32682" FT /evidence="ECO:0000250|UniProtKB:P29474" FT BINDING 374 FT /ligand="L-arginine" FT /ligand_id="ChEBI:CHEBI:32682" FT /evidence="ECO:0000250|UniProtKB:P29474" FT BINDING 378 FT /ligand="(6R)-L-erythro-5,6,7,8-tetrahydrobiopterin" FT /ligand_id="ChEBI:CHEBI:59560" FT /evidence="ECO:0000250|UniProtKB:P35228" FT BINDING 459 FT /ligand="(6R)-L-erythro-5,6,7,8-tetrahydrobiopterin" FT /ligand_id="ChEBI:CHEBI:59560" FT /evidence="ECO:0000250|UniProtKB:P35228" FT BINDING 460 FT /ligand="(6R)-L-erythro-5,6,7,8-tetrahydrobiopterin" FT /ligand_id="ChEBI:CHEBI:59560" FT /evidence="ECO:0000250|UniProtKB:P29474" FT BINDING 473 FT /ligand="(6R)-L-erythro-5,6,7,8-tetrahydrobiopterin" FT /ligand_id="ChEBI:CHEBI:59560" FT /evidence="ECO:0000250|UniProtKB:P29474" FT BINDING 488 FT /ligand="heme b" FT /ligand_id="ChEBI:CHEBI:60344" FT /evidence="ECO:0000250|UniProtKB:P29474" FT BINDING 542 FT /ligand="FMN" FT /ligand_id="ChEBI:CHEBI:58210" FT /evidence="ECO:0000250|UniProtKB:P35228" FT BINDING 543 FT /ligand="FMN" FT /ligand_id="ChEBI:CHEBI:58210" FT /evidence="ECO:0000250|UniProtKB:P35228" FT BINDING 544 FT /ligand="FMN" FT /ligand_id="ChEBI:CHEBI:58210" FT /evidence="ECO:0000250|UniProtKB:P35228" FT BINDING 546 FT /ligand="FMN" FT /ligand_id="ChEBI:CHEBI:58210" FT /evidence="ECO:0000250|UniProtKB:P35228" FT BINDING 547 FT /ligand="FMN" FT /ligand_id="ChEBI:CHEBI:58210" FT /evidence="ECO:0000250|UniProtKB:P35228" FT BINDING 588 FT /ligand="FMN" FT /ligand_id="ChEBI:CHEBI:58210" FT /evidence="ECO:0000250|UniProtKB:P35228" FT BINDING 589 FT /ligand="FMN" FT /ligand_id="ChEBI:CHEBI:58210" FT /evidence="ECO:0000250|UniProtKB:P35228" FT BINDING 625 FT /ligand="FMN" FT /ligand_id="ChEBI:CHEBI:58210" FT /evidence="ECO:0000250|UniProtKB:P35228" FT BINDING 632 FT /ligand="FMN" FT /ligand_id="ChEBI:CHEBI:58210" FT /evidence="ECO:0000250|UniProtKB:P35228" FT BINDING 658 FT /ligand="FMN" FT /ligand_id="ChEBI:CHEBI:58210" FT /evidence="ECO:0000250|UniProtKB:P35228" FT BINDING 662 FT /ligand="FMN" FT /ligand_id="ChEBI:CHEBI:58210" FT /evidence="ECO:0000250|UniProtKB:P35228" FT BINDING 747 FT /ligand="NADP(+)" FT /ligand_id="ChEBI:CHEBI:58349" FT /evidence="ECO:0000250|UniProtKB:P29476" FT BINDING 769 FT /ligand="FAD" FT /ligand_id="ChEBI:CHEBI:57692" FT /evidence="ECO:0000250|UniProtKB:P29476" FT BINDING 903 FT /ligand="FAD" FT /ligand_id="ChEBI:CHEBI:57692" FT /evidence="ECO:0000250|UniProtKB:P29476" FT BINDING 905 FT /ligand="FAD" FT /ligand_id="ChEBI:CHEBI:57692" FT /evidence="ECO:0000250|UniProtKB:P29476" FT BINDING 906 FT /ligand="FAD" FT /ligand_id="ChEBI:CHEBI:57692" FT /evidence="ECO:0000250|UniProtKB:P29476" FT BINDING 921 FT /ligand="FAD" FT /ligand_id="ChEBI:CHEBI:57692" FT /evidence="ECO:0000250|UniProtKB:P29476" FT BINDING 923 FT /ligand="FAD" FT /ligand_id="ChEBI:CHEBI:57692" FT /evidence="ECO:0000250|UniProtKB:P29476" FT BINDING 926 FT /ligand="NADP(+)" FT /ligand_id="ChEBI:CHEBI:58349" FT /evidence="ECO:0000250|UniProtKB:P29476" FT BINDING 927 FT /ligand="FAD" FT /ligand_id="ChEBI:CHEBI:57692" FT /evidence="ECO:0000250|UniProtKB:P29476" FT BINDING 940 FT /ligand="FAD" FT /ligand_id="ChEBI:CHEBI:57692" FT /evidence="ECO:0000250|UniProtKB:P29476" FT BINDING 941 FT /ligand="FAD" FT /ligand_id="ChEBI:CHEBI:57692" FT /evidence="ECO:0000250|UniProtKB:P29476" FT BINDING 942 FT /ligand="FAD" FT /ligand_id="ChEBI:CHEBI:57692" FT /evidence="ECO:0000250|UniProtKB:P29476" FT BINDING 981 FT /ligand="NADP(+)" FT /ligand_id="ChEBI:CHEBI:58349" FT /evidence="ECO:0000250|UniProtKB:P29476" FT BINDING 1014 FT /ligand="NADP(+)" FT /ligand_id="ChEBI:CHEBI:58349" FT /evidence="ECO:0000250|UniProtKB:P29476" FT BINDING 1043 FT /ligand="NADP(+)" FT /ligand_id="ChEBI:CHEBI:58349" FT /evidence="ECO:0000250|UniProtKB:P29476" FT BINDING 1044 FT /ligand="NADP(+)" FT /ligand_id="ChEBI:CHEBI:58349" FT /evidence="ECO:0000250|UniProtKB:P29476" FT BINDING 1050 FT /ligand="NADP(+)" FT /ligand_id="ChEBI:CHEBI:58349" FT /evidence="ECO:0000250|UniProtKB:P29476" FT BINDING 1052 FT /ligand="NADP(+)" FT /ligand_id="ChEBI:CHEBI:58349" FT /evidence="ECO:0000250|UniProtKB:P29476" FT BINDING 1054 FT /ligand="NADP(+)" FT /ligand_id="ChEBI:CHEBI:58349" FT /evidence="ECO:0000250|UniProtKB:P29476" FT BINDING 1087 FT /ligand="NADP(+)" FT /ligand_id="ChEBI:CHEBI:58349" FT /evidence="ECO:0000250|UniProtKB:P29476" FT MOD_RES 564 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:16641100" FT MOD_RES 572 FT /note="Phosphotyrosine" FT /evidence="ECO:0007744|PubMed:16641100" FT CONFLICT 10 FT /note="R -> K (in Ref. 7; BAA07994)" FT /evidence="ECO:0000305" FT CONFLICT 72 FT /note="H -> Y (in Ref. 1; BAA03138)" FT /evidence="ECO:0000305" FT CONFLICT 107 FT /note="C -> R (in Ref. 3; AAC13747)" FT /evidence="ECO:0000305" FT CONFLICT 128 FT /note="D -> V (in Ref. 8; BAA12035)" FT /evidence="ECO:0000305" FT CONFLICT 130 FT /note="P -> H (in Ref. 3; AAC13747)" FT /evidence="ECO:0000305" FT CONFLICT 171 FT /note="E -> G (in Ref. 8; BAA12035)" FT /evidence="ECO:0000305" FT CONFLICT 195 FT /note="P -> S (in Ref. 8; BAA12035)" FT /evidence="ECO:0000305" FT CONFLICT 248 FT /note="S -> N (in Ref. 9; AAC83553)" FT /evidence="ECO:0000305" FT CONFLICT 248 FT /note="S -> T (in Ref. 3 and 5)" FT /evidence="ECO:0000305" FT CONFLICT 264 FT /note="Y -> I (in Ref. 3; AAC13747)" FT /evidence="ECO:0000305" FT CONFLICT 271 FT /note="D -> A (in Ref. 9; AAC83554)" FT /evidence="ECO:0000305" FT CONFLICT 277 FT /note="D -> E (in Ref. 3; AAC13747)" FT /evidence="ECO:0000305" FT CONFLICT 348 FT /note="A -> P (in Ref. 1; BAA03138)" FT /evidence="ECO:0000305" FT CONFLICT 349 FT /note="V -> A (in Ref. 6; CAA54208)" FT /evidence="ECO:0000305" FT CONFLICT 380 FT /note="F -> L (in Ref. 2, 7, 8 and 9; AAC83553/AAC83554)" FT /evidence="ECO:0000305" FT CONFLICT 395 FT /note="R -> S (in Ref. 4; BAA02090)" FT /evidence="ECO:0000305" FT CONFLICT 399 FT /note="E -> G (in Ref. 9; AAC83553)" FT /evidence="ECO:0000305" FT CONFLICT 412 FT /note="V -> A (in Ref. 3; AAC13747)" FT /evidence="ECO:0000305" FT CONFLICT 477 FT /note="M -> I (in Ref. 13)" FT /evidence="ECO:0000305" FT CONFLICT 513 FT /note="T -> R (in Ref. 11; AAB18620)" FT /evidence="ECO:0000305" FT CONFLICT 515 FT /note="L -> W (in Ref. 12; AAB31028)" FT /evidence="ECO:0000305" FT CONFLICT 545 FT /note="G -> R (in Ref. 12; AAB31028)" FT /evidence="ECO:0000305" FT CONFLICT 551 FT /note="A -> R (in Ref. 11; AAB18620)" FT /evidence="ECO:0000305" FT CONFLICT 556 FT /note="A -> S (in Ref. 12; AAB31028)" FT /evidence="ECO:0000305" FT CONFLICT 559 FT /note="S -> T (in Ref. 9; AAC83553/AAC83554)" FT /evidence="ECO:0000305" FT CONFLICT 564 FT /note="T -> N (in Ref. 12; AAB31028)" FT /evidence="ECO:0000305" FT CONFLICT 570 FT /note="E -> D (in Ref. 12; AAB31028)" FT /evidence="ECO:0000305" FT CONFLICT 583 FT /note="L -> P (in Ref. 5 and 10)" FT /evidence="ECO:0000305" FT CONFLICT 591 FT /note="G -> A (in Ref. 12; AAB31028)" FT /evidence="ECO:0000305" FT CONFLICT 591 FT /note="G -> V (in Ref. 1 and 6)" FT /evidence="ECO:0000305" FT CONFLICT 619 FT /note="A -> R (in Ref. 2; AAA85861)" FT /evidence="ECO:0000305" FT CONFLICT 640 FT /note="Q -> P (in Ref. 9; AAC83553)" FT /evidence="ECO:0000305" FT CONFLICT 664 FT /note="D -> G (in Ref. 11; AAB18620)" FT /evidence="ECO:0000305" FT CONFLICT 679..680 FT /note="ET -> VP (in Ref. 1; BAA03138)" FT /evidence="ECO:0000305" FT CONFLICT 690 FT /note="Q -> P (in Ref. 11; AAB18620)" FT /evidence="ECO:0000305" FT CONFLICT 711 FT /note="S -> N (in Ref. 11; AAB18620)" FT /evidence="ECO:0000305" FT CONFLICT 714..715 FT /note="SL -> TR (in Ref. 11; AAB18620)" FT /evidence="ECO:0000305" FT CONFLICT 714 FT /note="S -> P (in Ref. 2, 7, 8, 9; AAC83553/AAC83554 and FT 10; AAC16401)" FT /evidence="ECO:0000305" FT CONFLICT 719 FT /note="K -> R (in Ref. 11; AAB18620)" FT /evidence="ECO:0000305" FT CONFLICT 721 FT /note="L -> P (in Ref. 6)" FT /evidence="ECO:0000305" FT CONFLICT 722 FT /note="S -> R (in Ref. 1, 6 and 11)" FT /evidence="ECO:0000305" FT CONFLICT 724..726 FT /note="IHA -> FLN (in Ref. 11)" FT /evidence="ECO:0000305" FT CONFLICT 730 FT /note="F -> I (in Ref. 11; AAB18620)" FT /evidence="ECO:0000305" FT CONFLICT 731 FT /note="T -> A (in Ref. 9; AAC83553)" FT /evidence="ECO:0000305" FT CONFLICT 740 FT /note="L -> P (in Ref. 6; CAA54208)" FT /evidence="ECO:0000305" FT CONFLICT 779 FT /note="A -> G (in Ref. 3; AAC13747)" FT /evidence="ECO:0000305" FT CONFLICT 834 FT /note="P -> S (in Ref. 8; BAA12035)" FT /evidence="ECO:0000305" FT CONFLICT 844 FT /note="A -> G (in Ref. 1; BAA03138)" FT /evidence="ECO:0000305" FT CONFLICT 895 FT /note="S -> L (in Ref. 4; BAA02090)" FT /evidence="ECO:0000305" FT CONFLICT 911 FT /note="Q -> L (in Ref. 3; AAC13747)" FT /evidence="ECO:0000305" FT CONFLICT 925 FT /note="V -> D (in Ref. 8; BAA12035)" FT /evidence="ECO:0000305" FT CONFLICT 937 FT /note="H -> N (in Ref. 9; AAC83554)" FT /evidence="ECO:0000305" FT CONFLICT 999 FT /note="H -> R (in Ref. 2, 7 and 9; AAC83553/AAC83554)" FT /evidence="ECO:0000305" FT CONFLICT 1008..1009 FT /note="TL -> NF (in Ref. 9; AAC83554)" FT /evidence="ECO:0000305" FT CONFLICT 1016 FT /note="P -> R (in Ref. 5)" FT /evidence="ECO:0000305" FT CONFLICT 1016 FT /note="P -> S (in Ref. 8)" FT /evidence="ECO:0000305" FT CONFLICT 1017 FT /note="E -> R (in Ref. 5 and 8)" FT /evidence="ECO:0000305" FT CONFLICT 1024 FT /note="E -> K (in Ref. 9; AAC83554)" FT /evidence="ECO:0000305" FT CONFLICT 1076 FT /note="L -> I (in Ref. 9; AAC83553)" FT /evidence="ECO:0000305" FT CONFLICT 1084 FT /note="M -> I (in Ref. 6; CAA54208)" FT /evidence="ECO:0000305" FT CONFLICT 1129 FT /note="F -> V (in Ref. 9; AAC83554)" FT /evidence="ECO:0000305" FT CONFLICT 1133 FT /note="A -> V (in Ref. 2, 7 and 9; AAC83553/AAC83554)" FT /evidence="ECO:0000305" FT CONFLICT 1138 FT /note="T -> A (in Ref. 2, 7 and 9; AAC83553/AAC83554)" FT /evidence="ECO:0000305" SQ SEQUENCE 1147 AA; 130628 MW; 77C77432DD8AB0A9 CRC64; MACPWKFLFR VKSYQGDLKE EKDINNNVEK TPGAIPSPTT QDDPKSHKHQ NGFPQFLTGT AQNVPESLDK LHVTPSTRPQ HVRIKNWGNG EIFHDTLHHK ATSDISCKSK LCMGSIMNSK SLTRGPRDKP TPVEELLPQA IEFINQYYGS FKEAKIEEHL ARLEAVTKEI ETTGTYQLTL DELIFATKMA WRNAPRCIGR IQWSNLQVFD ARSCSTASEM FQHICRHILY ATNSGNIRSA ITVFPQRSDG KHDFRIWNSQ LIRYAGYQMP DGTIRGDPAT LEFTQLCIDL GWKPRYGRFD VLPLVLQAHG QDPEVFEIPP DLVLEVTMEH PKYEWFQELG LKWYALPAVA NMLLEVGGLE FPACPFNGWY MGTEIGVRDF CDTQRYNILE EVGRRMGLET HTLASLWKDR AVTEINAAVL HSFQKQNVTI MDHHTASESF MKHMQNEYRA RGGCPADWIW LVPPVSGSIT PVFHQEMLNY VLSPFYYYQI EPWKTHIWQD EKLRPRRREI RFTVLVKAVF FASVLMRKVM ASRVRATVLF ATETGKSEAL ARDLAALFSY AFNTKVVCME QYKANTLEEE QLLLVVTSTF GNGDCPSNGQ TLKKSLFMMK ELGHTFRYAV FGLGSSMYPQ FCAFAHDIDQ KLSHLGASQL APTGEGDELS GQEDAFRSWA VQTFRAACET FDVRSKHCIQ IPKRYTSNAT WEPEQYKLTQ SPESLDLNKA LSSIHAKNVF TMRLKSLQNL QSEKSSRTTL LVQLTFEGSR GPSYLPGEHL GIFPGNQTAL VQGILERVVD CSSPDQTVCL EVLDESGSYW VKDKRLPPCS LRQALTYFLD ITTPPTQLQL HKLARFATEE THRQRLEALC QPSEYNDWKF SNNPTFLEVL EEFPSLRVPA AFLLSQLPIL KPRYYSISSS QDHTPSEVHL TVAVVTYRTR DGQGPLHHGV CSTWINNLKP EDPVPCFVRS VSGFQLPEDP SQPCILIGPG TGIAPFRSFW QQRLHDSQHR GLKGGRMTLV FGCRHPEEDH LYQEEMQEMV RKGVLFQVHT GYSRLPGKPK VYVQDILQKE LADEVFSVLH GEQGHLYVCG DVRMARDVAT TLKKLVAAKL NLSEEQVEDY FFQLKSQKRY HEDIFGAVFS YGAKKGNTLE EPKGTRL //