ID NGB_HUMAN Reviewed; 151 AA. AC Q9NPG2; DT 20-JUN-2003, integrated into UniProtKB/Swiss-Prot. DT 01-OCT-2000, sequence version 1. DT 27-MAR-2024, entry version 173. DE RecName: Full=Neuroglobin {ECO:0000303|PubMed:11029004}; DE AltName: Full=Nitrite reductase {ECO:0000305|PubMed:21296891}; DE EC=1.7.-.- {ECO:0000269|PubMed:21296891}; GN Name=NGB {ECO:0000312|HGNC:HGNC:14077}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA], SUBUNIT, AND TISSUE SPECIFICITY. RC TISSUE=Brain; RX PubMed=11029004; DOI=10.1038/35035093; RA Burmester T., Weich B., Reinhardt S., Hankeln T.; RT "A vertebrate globin expressed in the brain."; RL Nature 407:520-522(2000). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA]. RX PubMed=11820779; DOI=10.1006/bbrc.2002.6360; RA Zhang C.G., Wang C.L., Deng M.Y., Li L., Wang H.Y., Fan M., Xu W.L., RA Meng F.W., Qian L., He F.C.; RT "Full-length cDNA cloning of human neuroglobin and tissue expression of rat RT neuroglobin."; RL Biochem. Biophys. Res. Commun. 290:1411-1419(2002). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=12508121; DOI=10.1038/nature01348; RA Heilig R., Eckenberg R., Petit J.-L., Fonknechten N., Da Silva C., RA Cattolico L., Levy M., Barbe V., De Berardinis V., Ureta-Vidal A., RA Pelletier E., Vico V., Anthouard V., Rowen L., Madan A., Qin S., Sun H., RA Du H., Pepin K., Artiguenave F., Robert C., Cruaud C., Bruels T., RA Jaillon O., Friedlander L., Samson G., Brottier P., Cure S., Segurens B., RA Aniere F., Samain S., Crespeau H., Abbasi N., Aiach N., Boscus D., RA Dickhoff R., Dors M., Dubois I., Friedman C., Gouyvenoux M., James R., RA Madan A., Mairey-Estrada B., Mangenot S., Martins N., Menard M., Oztas S., RA Ratcliffe A., Shaffer T., Trask B., Vacherie B., Bellemere C., Belser C., RA Besnard-Gonnet M., Bartol-Mavel D., Boutard M., Briez-Silla S., RA Combette S., Dufosse-Laurent V., Ferron C., Lechaplais C., Louesse C., RA Muselet D., Magdelenat G., Pateau E., Petit E., Sirvain-Trukniewicz P., RA Trybou A., Vega-Czarny N., Bataille E., Bluet E., Bordelais I., Dubois M., RA Dumont C., Guerin T., Haffray S., Hammadi R., Muanga J., Pellouin V., RA Robert D., Wunderle E., Gauguet G., Roy A., Sainte-Marthe L., Verdier J., RA Verdier-Discala C., Hillier L.W., Fulton L., McPherson J., Matsuda F., RA Wilson R., Scarpelli C., Gyapay G., Wincker P., Saurin W., Quetier F., RA Waterston R., Hood L., Weissenbach J.; RT "The DNA sequence and analysis of human chromosome 14."; RL Nature 421:601-607(2003). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Brain; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [5] RP FUNCTION. RX PubMed=11473128; DOI=10.1074/jbc.m106438200; RA Dewilde S., Kiger L., Burmester T., Hankeln T., Baudin-Creuza V., Aerts T., RA Marden M.C., Caubergs R., Moens L.; RT "Biochemical characterization and ligand binding properties of neuroglobin, RT a novel member of the globin family."; RL J. Biol. Chem. 276:38949-38955(2001). RN [6] RP FUNCTION, MUTAGENESIS OF CYS-46; CYS-55 AND CYS-120, AND DISULFIDE BOND. RX PubMed=12860983; DOI=10.1074/jbc.m305519200; RA Wakasugi K., Nakano T., Morishima I.; RT "Oxidized human neuroglobin acts as a heterotrimeric Galpha protein guanine RT nucleotide dissociation inhibitor."; RL J. Biol. Chem. 278:36505-36512(2003). RN [7] RP DISULFIDE BOND. RX PubMed=15036292; DOI=10.1016/j.micron.2003.10.019; RA Hamdane D., Kiger L., Dewilde S., Green B.N., Pesce A., Uzan J., RA Burmester T., Hankeln T., Bolognesi M., Moens L., Marden M.C.; RT "Coupling of the heme and an internal disulfide bond in human RT neuroglobin."; RL Micron 35:59-62(2004). RN [8] RP FUNCTION. RX PubMed=18302932; DOI=10.1016/j.bbrc.2008.02.089; RA Watanabe S., Wakasugi K.; RT "Neuroprotective function of human neuroglobin is correlated with its RT guanine nucleotide dissociation inhibitor activity."; RL Biochem. Biophys. Res. Commun. 369:695-700(2008). RN [9] RP FUNCTION, CATALYTIC ACTIVITY, DISULFIDE BOND, AND MUTAGENESIS OF CYS-46; RP CYS-55 AND HIS-64. RX PubMed=21296891; DOI=10.1074/jbc.m110.159541; RA Tiso M., Tejero J., Basu S., Azarov I., Wang X., Simplaceanu V., RA Frizzell S., Jayaraman T., Geary L., Shapiro C., Ho C., Shiva S., RA Kim-Shapiro D.B., Gladwin M.T.; RT "Human neuroglobin functions as a redox-regulated nitrite reductase."; RL J. Biol. Chem. 286:18277-18289(2011). RN [10] RP PHOSPHORYLATION, INTERACTION WITH 14-3-3 PROTEINS, AND MUTAGENESIS OF RP SER-17 AND SER-50. RX PubMed=21965683; DOI=10.1074/jbc.m111.271973; RA Jayaraman T., Tejero J., Chen B.B., Blood A.B., Frizzell S., Shapiro C., RA Tiso M., Hood B.L., Wang X., Zhao X., Conrads T.P., Mallampalli R.K., RA Gladwin M.T.; RT "14-3-3 binding and phosphorylation of neuroglobin during hypoxia modulate RT six-to-five heme pocket coordination and rate of nitrite reduction to RT nitric oxide."; RL J. Biol. Chem. 286:42679-42689(2011). RN [11] {ECO:0007744|PDB:1OJ6} RP X-RAY CRYSTALLOGRAPHY (1.95 ANGSTROMS) IN COMPLEX WITH HEME B IN A RP HEXACOORDINATED FE(3+)-BOUND FORM, AND FUNCTION. RX PubMed=12962627; DOI=10.1016/s0969-2126(03)00166-7; RA Pesce A., Dewilde S., Nardini M., Moens L., Ascenzi P., Hankeln T., RA Burmester T., Bolognesi M.; RT "Human brain neuroglobin structure reveals a distinct mode of controlling RT oxygen affinity."; RL Structure 11:1087-1095(2003). RN [12] {ECO:0007744|PDB:4MPM} RP X-RAY CRYSTALLOGRAPHY (1.74 ANGSTROMS) IN COMPLEX WITH HEME B, DISULFIDE RP BONDS, AND FUNCTION. RX PubMed=24699645; DOI=10.1107/s1399004714000078; RA Guimaraes B.G., Hamdane D., Lechauve C., Marden M.C., RA Golinelli-Pimpaneau B.; RT "The crystal structure of wild-type human brain neuroglobin reveals RT flexibility of the disulfide bond that regulates oxygen affinity."; RL Acta Crystallogr. 70:1005-1014(2014). CC -!- FUNCTION: Monomeric globin with a bis-histidyl six-coordinate heme-iron CC atom through which it can bind dioxygen, carbon monoxide and nitric CC oxide (PubMed:11473128, PubMed:12962627, PubMed:24699645). Could help CC transport oxygen and increase its availability to the metabolically CC active neuronal tissues, though its low quantity in tissues as well as CC its high affinity for dioxygen, which may limit its oxygen-releasing CC ability, argue against it (PubMed:11473128, PubMed:12962627, CC PubMed:24699645, PubMed:12860983). The ferrous/deoxygenated form CC exhibits a nitrite reductase activity and it could produce nitric oxide CC which in turn inhibits cellular respiration in response to hypoxia CC (PubMed:21296891). In its ferrous/deoxygenated state, it may also CC exhibit GDI (Guanine nucleotide Dissociation Inhibitor) activity toward CC heterotrimeric G-alpha proteins, thereby regulating signal transduction CC to facilitate neuroprotective responses in the wake of hypoxia and CC associated oxidative stress (PubMed:12860983, PubMed:18302932). CC {ECO:0000269|PubMed:11473128, ECO:0000269|PubMed:12860983, CC ECO:0000269|PubMed:12962627, ECO:0000269|PubMed:18302932, CC ECO:0000269|PubMed:21296891, ECO:0000269|PubMed:24699645}. CC -!- CATALYTIC ACTIVITY: CC Reaction=Fe(III)-heme b-[protein] + H2O + nitric oxide = Fe(II)-heme b- CC [protein] + 2 H(+) + nitrite; Xref=Rhea:RHEA:77711, Rhea:RHEA- CC COMP:18975, Rhea:RHEA-COMP:18976, ChEBI:CHEBI:15377, CC ChEBI:CHEBI:15378, ChEBI:CHEBI:16301, ChEBI:CHEBI:16480, CC ChEBI:CHEBI:55376, ChEBI:CHEBI:60344; CC Evidence={ECO:0000269|PubMed:21296891}; CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:77713; CC Evidence={ECO:0000305|PubMed:21296891}; CC -!- SUBUNIT: Monomer (PubMed:11029004). Homodimer and homotetramer; CC disulfide-linked. Mainly monomeric but also detected as part of CC homodimers and homotetramers (By similarity). Interacts with 14-3-3 CC proteins; regulates the phosphorylation of NGB (PubMed:21965683). Could CC interact (ferrous form) with G-alpha(i) proteins (GTP-bound form) CC (PubMed:12860983). {ECO:0000250|UniProtKB:Q9ER97, CC ECO:0000269|PubMed:11029004, ECO:0000269|PubMed:12860983, CC ECO:0000269|PubMed:21965683}. CC -!- INTERACTION: CC Q9NPG2; Q9BX70: BTBD2; NbExp=3; IntAct=EBI-10311409, EBI-710091; CC Q9NPG2; Q6P1W5: C1orf94; NbExp=3; IntAct=EBI-10311409, EBI-946029; CC Q9NPG2; Q96D03: DDIT4L; NbExp=3; IntAct=EBI-10311409, EBI-742054; CC Q9NPG2; Q8WXI9: GATAD2B; NbExp=3; IntAct=EBI-10311409, EBI-923440; CC Q9NPG2; Q8IYA8: IHO1; NbExp=6; IntAct=EBI-10311409, EBI-8638439; CC Q9NPG2; Q96JM7: L3MBTL3; NbExp=3; IntAct=EBI-10311409, EBI-2686809; CC Q9NPG2; Q96JM7-2: L3MBTL3; NbExp=3; IntAct=EBI-10311409, EBI-11985629; CC Q9NPG2; A8MW99: MEI4; NbExp=3; IntAct=EBI-10311409, EBI-19944212; CC Q9NPG2; Q9GZT8: NIF3L1; NbExp=5; IntAct=EBI-10311409, EBI-740897; CC Q9NPG2; Q04864: REL; NbExp=3; IntAct=EBI-10311409, EBI-307352; CC Q9NPG2; Q04864-2: REL; NbExp=3; IntAct=EBI-10311409, EBI-10829018; CC Q9NPG2; P48775: TDO2; NbExp=6; IntAct=EBI-10311409, EBI-743494; CC Q9NPG2; Q96N21: TEPSIN; NbExp=3; IntAct=EBI-10311409, EBI-11139477; CC Q9NPG2; Q08AM6: VAC14; NbExp=6; IntAct=EBI-10311409, EBI-2107455; CC Q9NPG2; Q8N720: ZNF655; NbExp=3; IntAct=EBI-10311409, EBI-625509; CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol CC {ECO:0000250|UniProtKB:Q9ER97}. Mitochondrion matrix CC {ECO:0000250|UniProtKB:Q9ER97}. Note=Enriched in mitochondrial matrix CC upon oxygen-glucose deprivation. {ECO:0000250|UniProtKB:Q9ER97}. CC -!- TISSUE SPECIFICITY: Predominantly expressed in brain, the strongest CC expression is seen in the frontal lobe, the subthalamic nucleus and the CC thalamus. {ECO:0000269|PubMed:11029004}. CC -!- PTM: Phosphorylated during hypoxia by ERK1/ERK2. Phosphorylation CC regulates the heme pocket hexacoordination preventing the association CC of His-64 with the heme metal center. Thereby, promotes the access of CC dioxygen and nitrite to the heme and stimulates the nitrite reductase CC activity. Phosphorylation during hypoxia is stabilized by 14-3-3 CC proteins. {ECO:0000269|PubMed:21965683}. CC -!- PTM: An intramolecular Cys-46/Cys-55 disulfide bond, not necessarily CC present in orthologs, regulates the heme pocket hexacoordination CC preventing the association of His-64 with the heme metal center. CC Thereby, promotes the access of dioxygen and nitrite to the heme and CC stimulates the nitrite reductase activity. CC {ECO:0000269|PubMed:15036292, ECO:0000269|PubMed:21296891}. CC -!- SIMILARITY: Belongs to the globin family. {ECO:0000255|PROSITE- CC ProRule:PRU00238}. CC -!- WEB RESOURCE: Name=Wikipedia; Note=Neuroglobin entry; CC URL="https://en.wikipedia.org/wiki/Neuroglobin"; 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; AJ245944; CAC12994.1; -; Genomic_DNA. DR EMBL; AJ245946; CAC11133.1; -; mRNA. DR EMBL; AF422796; AAL98923.1; -; Genomic_DNA. DR EMBL; AF422797; AAL98924.1; -; mRNA. DR EMBL; AC007375; AAF63183.1; -; Genomic_DNA. DR EMBL; AC007954; AAF62557.1; -; Genomic_DNA. DR EMBL; BC032509; AAH32509.1; -; mRNA. DR CCDS; CCDS9856.1; -. DR RefSeq; NP_067080.1; NM_021257.3. DR PDB; 1OJ6; X-ray; 1.95 A; A/B/C/D=1-151. DR PDB; 4MPM; X-ray; 1.74 A; A/B=1-151. DR PDB; 7VQG; X-ray; 1.35 A; A=2-149. DR PDB; 8GRZ; X-ray; 2.00 A; A=1-151. DR PDBsum; 1OJ6; -. DR PDBsum; 4MPM; -. DR PDBsum; 7VQG; -. DR PDBsum; 8GRZ; -. DR AlphaFoldDB; Q9NPG2; -. DR BMRB; Q9NPG2; -. DR SMR; Q9NPG2; -. DR BioGRID; 121798; 186. DR IntAct; Q9NPG2; 16. DR STRING; 9606.ENSP00000298352; -. DR TCDB; 1.A.107.1.4; the pore-forming globin (globin) family. DR BioMuta; NGB; -. DR DMDM; 32171399; -. DR MassIVE; Q9NPG2; -. DR PaxDb; 9606-ENSP00000298352; -. DR PeptideAtlas; Q9NPG2; -. DR Antibodypedia; 25998; 317 antibodies from 30 providers. DR DNASU; 58157; -. DR Ensembl; ENST00000298352.5; ENSP00000298352.4; ENSG00000165553.5. DR GeneID; 58157; -. DR KEGG; hsa:58157; -. DR MANE-Select; ENST00000298352.5; ENSP00000298352.4; NM_021257.4; NP_067080.1. DR UCSC; uc001xtg.2; human. DR AGR; HGNC:14077; -. DR CTD; 58157; -. DR DisGeNET; 58157; -. DR GeneCards; NGB; -. DR HGNC; HGNC:14077; NGB. DR HPA; ENSG00000165553; Tissue enriched (brain). DR MIM; 605304; gene. DR neXtProt; NX_Q9NPG2; -. DR OpenTargets; ENSG00000165553; -. DR PharmGKB; PA31612; -. DR VEuPathDB; HostDB:ENSG00000165553; -. DR eggNOG; KOG3378; Eukaryota. DR GeneTree; ENSGT00510000048375; -. DR HOGENOM; CLU_003827_13_5_1; -. DR InParanoid; Q9NPG2; -. DR OMA; KAMRRGW; -. DR OrthoDB; 2015093at2759; -. DR PhylomeDB; Q9NPG2; -. DR TreeFam; TF333247; -. DR PathwayCommons; Q9NPG2; -. DR Reactome; R-HSA-8981607; Intracellular oxygen transport. DR SignaLink; Q9NPG2; -. DR BioGRID-ORCS; 58157; 14 hits in 1147 CRISPR screens. DR ChiTaRS; NGB; human. DR EvolutionaryTrace; Q9NPG2; -. DR GenomeRNAi; 58157; -. DR Pharos; Q9NPG2; Tbio. DR PRO; PR:Q9NPG2; -. DR Proteomes; UP000005640; Chromosome 14. DR RNAct; Q9NPG2; Protein. DR Bgee; ENSG00000165553; Expressed in right frontal lobe and 90 other cell types or tissues. DR ExpressionAtlas; Q9NPG2; baseline and differential. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0005739; C:mitochondrion; IEA:UniProtKB-SubCell. DR GO; GO:0043204; C:perikaryon; IEA:UniProtKB-SubCell. DR GO; GO:0005092; F:GDP-dissociation inhibitor activity; IDA:UniProtKB. DR GO; GO:0020037; F:heme binding; IEA:InterPro. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW. DR GO; GO:0098809; F:nitrite reductase activity; IDA:UniProtKB. DR GO; GO:0019825; F:oxygen binding; IDA:UniProtKB. DR GO; GO:0005344; F:oxygen carrier activity; IBA:GO_Central. DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW. DR GO; GO:0071456; P:cellular response to hypoxia; IMP:UniProtKB. DR GO; GO:0015671; P:oxygen transport; IBA:GO_Central. DR GO; GO:0001666; P:response to hypoxia; IBA:GO_Central. DR CDD; cd08920; Ngb; 1. DR Gene3D; 1.10.490.10; Globins; 1. DR InterPro; IPR000971; Globin. DR InterPro; IPR009050; Globin-like_sf. DR InterPro; IPR012292; Globin/Proto. DR PANTHER; PTHR46458; BLR2807 PROTEIN; 1. DR PANTHER; PTHR46458:SF19; NEUROGLOBIN; 1. DR Pfam; PF00042; Globin; 1. DR SUPFAM; SSF46458; Globin-like; 1. DR PROSITE; PS01033; GLOBIN; 1. DR Genevisible; Q9NPG2; HS. PE 1: Evidence at protein level; KW 3D-structure; Cytoplasm; Disulfide bond; Heme; Iron; Metal-binding; KW Mitochondrion; Oxidoreductase; Phosphoprotein; Reference proteome. FT CHAIN 1..151 FT /note="Neuroglobin" FT /id="PRO_0000053390" FT BINDING 64 FT /ligand="heme b" FT /ligand_id="ChEBI:CHEBI:60344" FT /ligand_part="Fe" FT /ligand_part_id="ChEBI:CHEBI:18248" FT /note="distal binding residue; reversible" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00238, FT ECO:0000269|PubMed:12962627, ECO:0000269|PubMed:24699645, FT ECO:0007744|PDB:1OJ6, ECO:0007744|PDB:4MPM" FT BINDING 96 FT /ligand="heme b" FT /ligand_id="ChEBI:CHEBI:60344" FT /ligand_part="Fe" FT /ligand_part_id="ChEBI:CHEBI:18248" FT /note="proximal binding residue" FT /evidence="ECO:0000269|PubMed:12962627, FT ECO:0000269|PubMed:24699645, ECO:0007744|PDB:1OJ6, FT ECO:0007744|PDB:4MPM" FT DISULFID 46..55 FT /note="Redox-active" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00238, FT ECO:0000269|PubMed:12860983, ECO:0000269|PubMed:15036292, FT ECO:0000269|PubMed:21296891, ECO:0000269|PubMed:24699645, FT ECO:0007744|PDB:4MPM" FT MUTAGEN 17 FT /note="S->A: No effect on interaction with 14-3-3 FT proteins." FT /evidence="ECO:0000269|PubMed:21965683" FT MUTAGEN 46 FT /note="C->A: Decreased nitrite reductase activity." FT /evidence="ECO:0000269|PubMed:21296891" FT MUTAGEN 46 FT /note="C->S: Loss of intramolecular disulfide bond." FT /evidence="ECO:0000269|PubMed:12860983" FT MUTAGEN 50 FT /note="S->A: Decreased interaction with 14-3-3 proteins." FT /evidence="ECO:0000269|PubMed:21965683" FT MUTAGEN 55 FT /note="C->A: Decreased affinity for nitrite. Decreased FT nitrite reductase activity." FT /evidence="ECO:0000269|PubMed:21296891" FT MUTAGEN 55 FT /note="C->S: Loss of intramolecular disulfide bond." FT /evidence="ECO:0000269|PubMed:12860983" FT MUTAGEN 64 FT /note="H->L,Q: Increased nitrite reductase activity." FT /evidence="ECO:0000269|PubMed:21296891" FT MUTAGEN 120 FT /note="C->S: No effect on disulfide bond." FT /evidence="ECO:0000269|PubMed:12860983" FT HELIX 6..13 FT /evidence="ECO:0007829|PDB:4MPM" FT TURN 14..18 FT /evidence="ECO:0007829|PDB:4MPM" FT HELIX 20..34 FT /evidence="ECO:0007829|PDB:4MPM" FT HELIX 38..49 FT /evidence="ECO:0007829|PDB:4MPM" FT HELIX 55..57 FT /evidence="ECO:0007829|PDB:4MPM" FT HELIX 59..77 FT /evidence="ECO:0007829|PDB:4MPM" FT HELIX 79..85 FT /evidence="ECO:0007829|PDB:4MPM" FT HELIX 86..98 FT /evidence="ECO:0007829|PDB:4MPM" FT HELIX 105..121 FT /evidence="ECO:0007829|PDB:4MPM" FT HELIX 122..124 FT /evidence="ECO:0007829|PDB:4MPM" FT HELIX 127..144 FT /evidence="ECO:0007829|PDB:4MPM" FT HELIX 145..148 FT /evidence="ECO:0007829|PDB:4MPM" SQ SEQUENCE 151 AA; 16933 MW; 45A292A7D77B9CE3 CRC64; MERPEPELIR QSWRAVSRSP LEHGTVLFAR LFALEPDLLP LFQYNCRQFS SPEDCLSSPE FLDHIRKVML VIDAAVTNVE DLSSLEEYLA SLGRKHRAVG VKLSSFSTVG ESLLYMLEKC LGPAFTPATR AAWSQLYGAV VQAMSRGWDG E //