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P29473 (NOS3_BOVIN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 165. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (2) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Nitric oxide synthase, endothelial

EC=1.14.13.39
Alternative name(s):
Constitutive NOS
Short name=cNOS
EC-NOS
Endothelial NOS
Short name=eNOS
NOS type III
Short name=NOSIII
Gene names
Name:NOS3
OrganismBos taurus (Bovine) [Reference proteome]
Taxonomic identifier9913 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaLaurasiatheriaCetartiodactylaRuminantiaPecoraBovidaeBovinaeBos

Protein attributes

Sequence length1205 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Produces nitric oxide (NO) which is implicated in vascular smooth muscle relaxation through a cGMP-mediated signal transduction pathway. NO mediates vascular endothelial growth factor (VEGF)-induced angiogenesis in coronary vessels and promotes blood clotting through the activation of platelets.

Catalytic activity

2 L-arginine + 3 NADPH + 4 O2 = 2 L-citrulline + 2 nitric oxide + 3 NADP+ + 4 H2O.

Cofactor

Heme group.

Binds 1 FAD.

Binds 1 FMN.

Tetrahydrobiopterin (BH4). May stabilize the dimeric form of the enzyme.

Enzyme regulation

Stimulated by calcium/calmodulin. Inhibited by NOSIP and NOSTRIN By similarity.

Subunit structure

Homodimer. Interacts with NOSIP and NOSTRIN By similarity.

Subcellular location

Cell membrane. Membranecaveola. Cytoplasmcytoskeleton By similarity. Golgi apparatus. Note: Specifically associates with actin cytoskeleton in the G2 phase of the cell cycle; which is favored by interaction with NOSIP and results in a reduced enzymatic activity By similarity. Ref.7

Post-translational modification

Phosphorylation by AMPK at Ser-1179 in the presence of Ca2+-calmodulin (CaM) activates activity. In absence of Ca2+-calmodulin, AMPK also phosphorylates Thr-497, resulting in inhibition of activity. Phosphorylation of Ser-116 by CDK5 reduces activity By similarity.

Sequence similarities

Belongs to the NOS family.

Contains 1 FAD-binding FR-type domain.

Contains 1 flavodoxin-like domain.

Ontologies

Keywords
   Biological processBlood coagulation
Hemostasis
   Cellular componentCell membrane
Cytoplasm
Cytoskeleton
Golgi apparatus
Membrane
   LigandCalcium
Calmodulin-binding
FAD
Flavoprotein
FMN
Heme
Iron
Metal-binding
NADP
Zinc
   Molecular functionOxidoreductase
   PTMLipoprotein
Myristate
Palmitate
Phosphoprotein
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processarginine catabolic process

Inferred from direct assay PubMed 11085984. Source: BHF-UCL

blood coagulation

Inferred from electronic annotation. Source: UniProtKB-KW

mitochondrion organization

Inferred from mutant phenotype PubMed 12574632. Source: BHF-UCL

negative regulation of extrinsic apoptotic signaling pathway via death domain receptors

Inferred from mutant phenotype PubMed 11085984. Source: BHF-UCL

nitric oxide biosynthetic process

Inferred from direct assay PubMed 11085984PubMed 21106532. Source: BHF-UCL

positive regulation of guanylate cyclase activity

Inferred from mutant phenotype PubMed 11085984. Source: BHF-UCL

   Cellular_componentGolgi apparatus

Inferred from direct assay PubMed 11085984. Source: BHF-UCL

caveola

Inferred from electronic annotation. Source: UniProtKB-SubCell

cytoskeleton

Inferred from electronic annotation. Source: UniProtKB-SubCell

   Molecular_functionFMN binding

Inferred from electronic annotation. Source: InterPro

NADP binding

Inferred from electronic annotation. Source: InterPro

flavin adenine dinucleotide binding

Inferred from electronic annotation. Source: InterPro

heme binding

Inferred from electronic annotation. Source: InterPro

iron ion binding

Inferred from electronic annotation. Source: InterPro

nitric-oxide synthase activity

Inferred from direct assay PubMed 11085984PubMed 9843699. Source: BHF-UCL

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Initiator methionine11Removed
Chain2 – 12051204Nitric oxide synthase, endothelial
PRO_0000170941

Regions

Domain522 – 705184Flavodoxin-like
Domain758 – 1004247FAD-binding FR-type
Nucleotide binding651 – 68232FMN By similarity
Nucleotide binding795 – 80612FAD By similarity
Nucleotide binding937 – 94711FAD By similarity
Nucleotide binding1012 – 103019NADP By similarity
Nucleotide binding1110 – 112516NADP By similarity
Region100 – 488389Interaction with NOSIP By similarity
Region492 – 51221Calmodulin-binding Potential

Sites

Metal binding961Zinc
Metal binding1011Zinc
Metal binding1861Iron (heme axial ligand)

Amino acid modifications

Modified residue1161Phosphoserine; by CDK5 By similarity
Modified residue1431Phosphoserine; by PKA
Modified residue4971Phosphothreonine; by AMPK and PKA Ref.6
Modified residue6351Phosphoserine Ref.6
Modified residue11771Phosphothreonine By similarity
Modified residue11791Phosphoserine; by AMPK, PDPK1 and PKA Ref.6
Lipidation21N-myristoyl glycine Ref.4
Lipidation151S-palmitoyl cysteine Ref.5
Lipidation261S-palmitoyl cysteine Ref.5

Experimental info

Sequence conflict1001C → R in AAA30669. Ref.3
Sequence conflict1651Y → I in AAA30669. Ref.3
Sequence conflict318 – 32811EHPTLEWFAAL → GAPHTGVVRGP in AAA30669. Ref.3
Sequence conflict4551S → Y in AAA30669. Ref.3
Sequence conflict4591T → P in AAA30669. Ref.3
Sequence conflict7411T → A in AAA30669. Ref.3
Sequence conflict804 – 8052CP → SA in AAA30669. Ref.3
Sequence conflict8571L → V in AAA30669. Ref.3
Sequence conflict907 – 9082WF → LV in AAA30669. Ref.3
Sequence conflict10421A → H in AAA30669. Ref.3

Secondary structure

...................................................................................... 1205
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
P29473 [UniParc].

Last modified January 23, 2007. Version 3.
Checksum: 5DC8FF4F25870281

FASTA1,205133,287
        10         20         30         40         50         60 
MGNLKSVGQE PGPPCGLGLG LGLGLCGKQG PASPAPEPSR APAPATPHAP DHSPAPNSPT 

        70         80         90        100        110        120 
LTRPPEGPKF PRVKNWELGS ITYDTLCAQS QQDGPCTPRC CLGSLVLPRK LQTRPSPGPP 

       130        140        150        160        170        180 
PAEQLLSQAR DFINQYYSSI KRSGSQAHEE RLQEVEAEVA STGTYHLRES ELVFGAKQAW 

       190        200        210        220        230        240 
RNAPRCVGRI QWGKLQVFDA RDCSSAQEMF TYICNHIKYA TNRGNLRSAI TVFPQRAPGR 

       250        260        270        280        290        300 
GDFRIWNSQL VRYAGYRQQD GSVRGDPANV EITELCIQHG WTPGNGRFDV LPLLLQAPDE 

       310        320        330        340        350        360 
APELFVLPPE LVLEVPLEHP TLEWFAALGL RWYALPAVSN MLLEIGGLEF SAAPFSGWYM 

       370        380        390        400        410        420 
STEIGTRNLC DPHRYNILED VAVCMDLDTR TTSSLWKDKA AVEINLAVLH SFQLAKVTIV 

       430        440        450        460        470        480 
DHHAATVSFM KHLDNEQKAR GGCPADWAWI VPPISGSLTP VFHQEMVNYI LSPAFRYQPD 

       490        500        510        520        530        540 
PWKGSATKGA GITRKKTFKE VANAVKISAS LMGTLMAKRV KATILYASET GRAQSYAQQL 

       550        560        570        580        590        600 
GRLFRKAFDP RVLCMDEYDV VSLEHEALVL VVTSTFGNGD PPENGESFAA ALMEMSGPYN 

       610        620        630        640        650        660 
SSPRPEQHKS YKIRFNSVSC SDPLVSSWRR KRKESSNTDS AGALGTLRFC VFGLGSRAYP 

       670        680        690        700        710        720 
HFCAFARAVD TRLEELGGER LLQLGQGDEL CGQEEAFRGW AKAAFQASCE TFCVGEEAKA 

       730        740        750        760        770        780 
AAQDIFSPKR SWKRQRYRLS TQAEGLQLLP GLIHVHRRKM FQATVLSVEN LQSSKSTRAT 

       790        800        810        820        830        840 
ILVRLDTAGQ EGLQYQPGDH IGICPPNRPG LVEALLSRVE DPPPPTESVA VEQLEKGSPG 

       850        860        870        880        890        900 
GPPPSWVRDP RLPPCTLRQA LTFFLDITSP PSPRLLRLLS TLAEEPSEQQ ELETLSQDPR 

       910        920        930        940        950        960 
RYEEWKWFRC PTLLEVLEQF PSVALPAPLL LTQLPLLQPR YYSVSSAPNA HPGEVHLTVA 

       970        980        990       1000       1010       1020 
VLAYRTQDGL GPLHYGVCST WLSQLKTGDP VPCFIRGAPS FRLPPDPYVP CILVGPGTGI 

      1030       1040       1050       1060       1070       1080 
APFRGFWQER LHDIESKGLQ PAPMTLVFGC RCSQLDHLYR DEVQDAQERG VFGRVLTAFS 

      1090       1100       1110       1120       1130       1140 
REPDSPKTYV QDILRTELAA EVHRVLCLER GHMFVCGDVT MATSVLQTVQ RILATEGDME 

      1150       1160       1170       1180       1190       1200 
LDEAGDVIGV LRDQQRYHED IFGLTLRTQE VTSRIRTQSF SLQERHLRGA VPWAFDPPGP 


DTPGP 

« Hide

References

[1]"Endothelial nitric oxide synthase: molecular cloning and characterization of a distinct constitutive enzyme isoform."
Lamas S., Marsden P.A., Li G.K., Tempst P., Michel T.
Proc. Natl. Acad. Sci. U.S.A. 89:6348-6352(1992) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]"Molecular cloning and characterization of the constitutive bovine aortic endothelial cell nitric oxide synthase."
Nishida K., Harrison D.G., Navas J.P., Fisher A.A., Dockery S.P., Uematsu M., Nerem R.M., Alexander R.W., Murphy T.J.
J. Clin. Invest. 90:2092-2096(1992) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[3]"Molecular cloning and expression of a cDNA encoding endothelial cell nitric oxide synthase."
Sessa W.C., Harrison J.K., Barber C.M., Zeng D., Durieux M.E., D'Angelo D.D., Lynch K.R., Peach M.J.
J. Biol. Chem. 267:15274-15276(1992) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
Tissue: Aortic endothelium.
[4]"Endothelial nitric oxide synthase. N-terminal myristoylation determines subcellular localization."
Busconi L., Michel T.
J. Biol. Chem. 268:8410-8413(1993) [PubMed] [Europe PMC] [Abstract]
Cited for: MYRISTOYLATION AT GLY-2.
[5]"Mutagenesis of palmitoylation sites in endothelial nitric oxide synthase identifies a novel motif for dual acylation and subcellular targeting."
Robinson L.J., Michel T.
Proc. Natl. Acad. Sci. U.S.A. 92:11776-11780(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: PALMITOYLATION AT CYS-15 AND CYS-26.
[6]"Shear stress stimulates phosphorylation of eNOS at Ser(635) by a protein kinase A-dependent mechanism."
Boo Y.C., Hwang J., Sykes M., Michell B.J., Kemp B.E., Lum H., Jo H.
Am. J. Physiol. 283:H1819-H1828(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT THR-497; SER-635 AND SER-1179.
[7]"Aberrant cytoplasmic sequestration of eNOS in endothelial cells after monocrotaline, hypoxia, and senescence: live-cell caveolar and cytoplasmic NO imaging."
Mukhopadhyay S., Xu F., Sehgal P.B.
Am. J. Physiol. 292:H1373-H1389(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBCELLULAR LOCATION.
[8]"Crystal structure of constitutive endothelial nitric oxide synthase: a paradigm for pterin function involving a novel metal center."
Raman C.S., Li H., Martasek P., Kral V., Masters B.S.S., Poulos T.L.
Cell 95:939-950(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 67-482.
[9]"Mapping the active site polarity in structures of endothelial nitric oxide synthase heme domain complexed with isothioureas."
Li H., Raman C.S., Martasek P., Kral V., Masters B.S.S., Poulos T.L.
J. Inorg. Biochem. 81:133-139(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (1.86 ANGSTROMS) OF 67-482.
[10]"Crystallographic studies on endothelial nitric oxide synthase complexed with nitric oxide and mechanism-based inhibitors."
Li H., Raman C.S., Martasek P., Masters B.S.S., Poulos T.L.
Biochemistry 40:5399-5406(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (1.93 ANGSTROMS).
[11]"Crystal structure of nitric oxide synthase bound to nitro indazole reveals a novel inactivation mechanism."
Raman C.S., Li H., Martasek P., Southan G., Masters B.S.S., Poulos T.L.
Biochemistry 40:13448-13455(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (1.65 ANGSTROMS).
[12]"Implications for isoform-selective inhibitor design derived from the binding mode of bulky isothioureas to the heme domain of endothelial nitric-oxide synthase."
Raman C.S., Li H., Martasek P., Babu B.R., Griffith O.W., Southan G., Masters B.S.S., Poulos T.L.
J. Biol. Chem. 276:26486-26491(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (1.93 ANGSTROMS).
[13]"Structural basis for pterin antagonism in nitric-oxide synthase. Development of novel 4-oxo-pteridine antagonists of (6R)-5,6,7,8-tetrahydrobiopterin."
Kotsonis P., Frohlich L.G., Raman C.S., Li H., Berg M., Gerwig R., Groehn V., Kang Y., Al-Masoudi N., Taghavi-Moghadam S., Mohr D., Munch U., Schnabel J., Martasek P., Masters B.S.S., Strobel H., Poulos T., Matter H., Pfleiderer W., Schmidt H.H.H.W.
J. Biol. Chem. 276:49133-49141(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.35 ANGSTROMS).
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
M99057 mRNA. Translation: AAA30667.1.
M89952 mRNA. Translation: AAA30494.1.
M95674 mRNA. Translation: AAA30669.1.
PIRA38943.
UniGeneBt.4662.

3D structure databases

PDBe
RCSB-PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
1D0CX-ray1.65A/B39-482[»]
1D0OX-ray1.95A/B39-482[»]
1D1VX-ray1.93A/B39-482[»]
1D1WX-ray2.00A/B39-482[»]
1D1XX-ray2.00A/B39-482[»]
1D1YX-ray2.20A/B39-482[»]
1DM6X-ray1.95A/B39-482[»]
1DM7X-ray2.10A/B39-482[»]
1DM8X-ray2.25A/B39-482[»]
1DMIX-ray2.00A/B39-482[»]
1DMJX-ray2.35A/B39-482[»]
1DMKX-ray1.90A/B39-482[»]
1ED4X-ray1.86A/B39-482[»]
1ED5X-ray1.80A/B39-482[»]
1ED6X-ray2.05A/B39-482[»]
1FOIX-ray1.93A/B39-482[»]
1FOJX-ray2.10A/B39-482[»]
1FOLX-ray2.20A/B39-482[»]
1FOOX-ray2.00A/B39-482[»]
1FOPX-ray2.30A/B39-482[»]
1I83X-ray2.00A/B39-482[»]
1NSEX-ray1.90A/B39-482[»]
1P6LX-ray2.35A/B67-483[»]
1P6MX-ray2.27A/B67-483[»]
1P6NX-ray2.50A/B67-483[»]
1Q2OX-ray1.74A/B67-482[»]
1RS8X-ray2.30A/B67-482[»]
1RS9X-ray2.22A/B67-482[»]
1ZZSX-ray1.85A/B67-482[»]
1ZZTX-ray2.14A/B67-482[»]
2G6OX-ray1.90A/B67-482[»]
2HX2X-ray1.95A/B67-482[»]
2NSEX-ray2.34A/B39-482[»]
3DQSX-ray2.03A/B67-482[»]
3DQTX-ray2.54A/B67-482[»]
3E7SX-ray2.50A/B57-487[»]
3JWWX-ray2.20A/B39-482[»]
3JWXX-ray2.00A/B39-482[»]
3JWYX-ray2.24A/B39-482[»]
3JWZX-ray2.40A/B39-482[»]
3N5PX-ray2.39A/B39-482[»]
3N5QX-ray2.90A/B39-482[»]
3N5RX-ray2.57A/B39-482[»]
3N5SX-ray2.18A/B39-482[»]
3N5TX-ray2.52A/B39-482[»]
3NLDX-ray2.28A/B39-482[»]
3NLEX-ray1.95A/B39-482[»]
3NLFX-ray2.32A/B39-482[»]
3NLGX-ray2.38A/B39-482[»]
3NLHX-ray2.10A/B39-482[»]
3NLIX-ray1.98A/B39-482[»]
3NLTX-ray2.74A/B39-482[»]
3NLUX-ray2.65A/B39-482[»]
3NSEX-ray2.10A/B39-482[»]
3PNHX-ray1.93A/B67-482[»]
3RQOX-ray2.08A/B40-482[»]
3RQPX-ray2.35A/B40-482[»]
4C3AX-ray2.20A/B40-482[»]
4CARX-ray2.05A/B40-482[»]
4CFTX-ray1.79A/B40-482[»]
4CTYX-ray2.30A/B40-482[»]
4CTZX-ray2.01A/B40-482[»]
4CU0X-ray2.08A/B40-482[»]
4CU1X-ray1.89A/B40-482[»]
4IMXX-ray2.25A/B40-482[»]
4JSKX-ray2.28A/B40-482[»]
4JSLX-ray2.04A/B40-482[»]
4JSMX-ray2.25A/B40-482[»]
4K5HX-ray2.25A/B40-482[»]
4K5IX-ray2.08A/B40-482[»]
4K5JX-ray2.36A/B40-482[»]
4K5KX-ray2.00A/B40-482[»]
4KCPX-ray2.07A/B40-482[»]
4KCQX-ray2.03A/B40-482[»]
4KCRX-ray2.09A/B40-482[»]
4KCSX-ray2.05A/B40-482[»]
4LUWX-ray2.25A/B41-482[»]
4NSEX-ray1.95A/B39-482[»]
5NSEX-ray1.90A/B39-482[»]
6NSEX-ray2.35A/B39-482[»]
7NSEX-ray2.35A/B39-482[»]
8NSEX-ray2.25A/B39-482[»]
9NSEX-ray2.24A/B39-482[»]
ProteinModelPortalP29473.
SMRP29473. Positions 67-482, 731-1164.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

DIPDIP-42217N.
MINTMINT-1347838.
STRING9913.ENSBTAP00000023515.

Chemistry

BindingDBP29473.
ChEMBLCHEMBL4802.

Proteomic databases

PRIDEP29473.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Phylogenomic databases

eggNOGCOG4362.
HOGENOMHOG000220884.
HOVERGENHBG000159.
InParanoidP29473.

Family and domain databases

Gene3D1.20.990.10. 1 hit.
3.40.50.360. 2 hits.
3.90.340.10. 1 hit.
InterProIPR003097. FAD-binding_1.
IPR017927. Fd_Rdtase_FAD-bd.
IPR001094. Flavdoxin.
IPR008254. Flavodoxin/NO_synth.
IPR001709. Flavoprot_Pyr_Nucl_cyt_Rdtase.
IPR029039. Flavoprotein-like.
IPR023173. NADPH_Cyt_P450_Rdtase_dom3.
IPR004030. NO_synthase_oxygenase_dom.
IPR012144. NOS_euk.
IPR001433. OxRdtase_FAD/NAD-bd.
IPR017938. Riboflavin_synthase-like_b-brl.
[Graphical view]
PfamPF00667. FAD_binding_1. 1 hit.
PF00258. Flavodoxin_1. 1 hit.
PF00175. NAD_binding_1. 1 hit.
PF02898. NO_synthase. 1 hit.
[Graphical view]
PIRSFPIRSF000333. NOS. 1 hit.
PRINTSPR00369. FLAVODOXIN.
PR00371. FPNCR.
SUPFAMSSF52218. SSF52218. 1 hit.
SSF56512. SSF56512. 1 hit.
SSF63380. SSF63380. 1 hit.
PROSITEPS51384. FAD_FR. 1 hit.
PS50902. FLAVODOXIN_LIKE. 1 hit.
PS60001. NOS. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

EvolutionaryTraceP29473.
NextBio20806546.

Entry information

Entry nameNOS3_BOVIN
AccessionPrimary (citable) accession number: P29473
Entry history
Integrated into UniProtKB/Swiss-Prot: April 1, 1993
Last sequence update: January 23, 2007
Last modified: July 9, 2014
This is version 165 of the entry and version 3 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references